In June 2002, Mysterio signed with World Wrestling Entertainment (WWE), and promos that hyped his debut began airing.
Mysterio made his WWE debut on the July 25, 2002 episode of SmackDown! as a fan favorite in a match against Chavo Guerrero, which Mysterio won. He eventually began a feud with Kurt Angle, which culminated in a match at SummerSlam that Angle won after forcing Mysterio to submit to the ankle lock. He later formed a tag team with Edge; the two participated in a tournament for the newly created and SmackDown!-exclusive WWE Tag Team Championship. They lost to Kurt Angle and Chris Benoit in the finals of the tournament at No Mercy; the match was voted match of the year by the Wrestling Observer Newsletter. After they failed in winning the title, Mysterio and Edge defeated Los Guerreros in a number one contender's match on the October 24 episode of SmackDown! to earn a title shot. On the November 7 episode of SmackDown!, they defeated Angle and Benoit in a two out of three falls match to win their first Tag Team Championship. They soon lost the tag titles to Los Guerreros in a Triple Threat Elimination match that also involved former champions Angle and Benoit at Survivor Series. Shortly after the loss, Mysterio and Edge disbanded as a tag team.
On the March 6, 2003 episode of SmackDown!, Mysterio defeated Tajiri and Jamie Noble in a Triple Threat match to earn a shot at the WWE Cruiserweight Championship. At WrestleMania XIX, he challenged the champion, Matt Hardy, for the title but lost after Shannon Moore interfered. On the May 22 episode of SmackDown!, Mysterio defeated Shannon Moore and Crash Holly in a Handicap Elimination match to become the number one contender for the Cruiserweight title. On the June 5 episode of SmackDown!, he defeated Hardy to win his sixth Cruiserweight Championship. Mysterio's reign ended when he lost the title to Tajiri on the September 25 episode of SmackDown!.
On the January 1, 2004 episode of SmackDown!, Mysterio defeated Tajiri to win his seventh Cruiserweight Championship. After a successful title defense against Jamie Noble at Royal Rumble, Mysterio lost the title to Chavo Guerrero at No Way Out in February. At WrestleMania XX, Mysterio took part in a Cruiserweight Open for the title, but lost as Chavo retained the title. On the June 17 episode of SmackDown!, he defeated Chavo Classic for a record-setting eighth Cruiserweight Championship. He successfully defended the title against Classic's son Chavo Guerrero at The Great American Bash. While Mysterio was Cruiserweight Champion, Spike Dudley turned heel after plowing Mysterio through a table and joined the other Dudleys before winning the Cruiserweight Title from Mysterio on the July 29 episode of SmackDown!. At Survivor Series, he participated in a Fatal Four-Way match for the Cruiserweight Title involving the champion Spike, Chavo Guerrero, and Billy Kidman. Mysterio lost when Dudley pinned Guerrero to retain.
Rey Mysterio had a tag team with Eddie and they were also best friends. After an unsuccessful attempt at regaining the Cruiserweight Title, Mysterio formed a tag team with Rob Van Dam, and went on to win the Tag Team Championship from Kenzo Suzuki and René Dupreé on the December 9 episode of SmackDown!. They successfully defended the title against the former champions at Armageddon, before losing the title to the Basham Brothers on the January 13, 2005 episode of SmackDown! after Van Dam was injured.
Mysterio then teamed up with Eddie Guerrero to win the Tag Team Championship back from the Bashams at No Way Out. During this time Rey had a video camera, which was called the "619 cam", during his entrance he taped members of the audience with this. In a departure from traditional booking, the new champions did not defend their title at WrestleMania 21, but instead had a match against each other which Rey won. Two months later, at ECW One Night Stand, Mysterio faced and defeated long-time rival Psicosis.
The match at WrestleMania was part of a storyline in which Guerrero turned on Mysterio and beat him up after abandoning him during a match against MNM for the Tag Team Championship. Then after a no disqualification match against Chavo, Eddie came out and slammed Mysterio on the steel steps, displaying Eddie's increasing frustration with being unable to defeat Mysterio. Guerrero and Mysterio continued to feud, with Guerrero threatening to reveal a secret he and Mysterio shared involving Mysterio's real life son Dominick, unless Mysterio deferred to Guerrero's authority. Guerrero later revealed that, in the storyline, he was Dominick's biological father. The storyline went that Guerrero knew Mysterio was having trouble starting his own family, so Guerrero left Dominick as a baby with Mysterio and his wife Angie to raise. In subsequent weeks, Guerrero threatened to take custody of Dominick, drawing up custody papers and having his lawyer present them to Mysterio. At SummerSlam, Mysterio defeated Guerrero in a ladder match for the custody of Dominick. Their feud ended when Guerrero gained a victory over Mysterio in a steel cage match. On November 13, 2005, Eddie Guerrero was found dead in his hotel room in Minneapolis, Minnesota. That same day at a WWE "Super Show" where SmackDown! and Raw were both taped, Mysterio gave an emotional speech about Eddie, and in a show of respect removed his mask (though he put his head down, so no one could see his face). Mysterio went on to defeat Shawn Michaels in an interpromotional match later that night. After the match, Michaels and Mysterio hugged in the ring and Mysterio pointed up to the sky, crying, in memory of Guerrero.
Mysterio participated in the main event of Survivor Series as part of Team SmackDown! along with Randy Orton, Bobby Lashley, Batista, and JBL who defeated Team Raw (Shawn Michaels, Kane, The Big Show, Carlito, and Chris Masters). After Survivor Series, Mysterio faced Big Show in a match billed as "David vs. Goliath" in a SmackDown! special show. The match stemmed from Mysterio eliminating Big Show at Survivor Series, and ended as a "no contest" when Big Show's tag team partner Kane interfered in the match. Mysterio continued to feud with Raw's World Tag Team Champions, even finding a tag team partner in World Heavyweight Champion Batista who, along with Mysterio, would be set to face Raw's Kane and The Big Show in a tag match at Armageddon. Before Armageddon, Batista and Mysterio defeated Mysterio's longtime rivals MNM on the December 19 episode of SmackDown! to win the Tag Team Championship in a match they both dedicated to Eddie Guerrero. Now the Tag Team Champions, Mysterio and Batista's match with Big Show and Kane was billed as "Champions vs. Champions." At Armageddon, Mysterio and Batista lost this "Raw vs. SmackDown!" match when Kane pinned Mysterio after a chokeslam. On the December 30 episode of SmackDown!, MNM invoked their rematch clause, defeating Batista and Mysterio with help from Mark Henry to regain the Tag Team Championship. Mysterio and Batista lost a Steel Cage match in an effort to reclaim the titles the following week, again courtesy of interference by Henry. On the January 10 episode of SmackDown!, Mysterio was involved in a 20 man battle royal for the vacant World Heavyweight Championship. He was eliminated by Mark Henry, Kurt Angle came out on top by eliminating Henry to win the World Heavyweight title.
At the 2006 Royal Rumble match, Mysterio entered as the number 2 entry. He would go on to win the match and earn a world title shot, last eliminating Randy Orton, he lasted 62 minutes making him the person to be the longest lasting competitor in the Royal Rumble. Orton urged him to put the title shot at stake in a match at No Way Out. In the weeks preceding No Way Out, Orton made disparaging remarks about Eddie Guerrero. Many fans felt the comments were unwarranted and highly distasteful so soon after Guerrero's death in November 2005. Orton won at No Way Out, earning Mysterio's title shot for the World Heavyweight Championship at WrestleMania 22. General Manager Theodore Long re-added Mysterio to the WrestleMania 22 title match, however, making it a Triple Threat match between Orton, Mysterio, and then-champion, Kurt Angle. At Wrestlemania 22, Mysterio pinned Randy Orton to become the new World Heavyweight Champion. On the April 7 episode of SmackDown!, Mysterio – who was billed as being an "underdog champion", made his first successful World Heavyweight title defense against Randy Orton. Mysterio went on to retain his title again during a WrestleMania rematch on SmackDown! against Kurt Angle, three weeks later. The week before the title defense took place saw the start of a feud between the then-United States Champion John "Bradshaw" Layfield and Mysterio. The rivalry kicked off after JBL stated he deserved the World Heavyweight title during his celebration of becoming the U.S. Champion. The feud with JBL saw Mysterio face off against any opponent of JBL's choosing in the three weeks leading up to his title match against Mysterio at Judgment Day. Mysterio was defeated by Mark Henry and The Great Khali in separate non-title matches before wrestling Kane to a "no contest"; Mysterio retained his title against JBL at Judgement Day. The feud intensified when JBL lost the U.S. Title to Bobby Lashley five days later on SmackDown! after being tricked by Mysterio to take on all comers like he himself had. This led JBL to vow that if he did not win his rematch against Mysterio, he would quit SmackDown!. In the main event of the evening, Mysterio retained the World Heavyweight Championship, causing JBL to leave SmackDown!, until ECW One Night Stand, when JBL announced he would return as a color commentator.
It was revealed that Mysterio would have to defend his title against ECW wrestler Sabu at One Night Stand. In the weeks leading up to his title defense, Mysterio defeated Cruiserweight Champion Gregory Helms in a Champion vs. Champion match but was defeated by Rob Van Dam at WWE vs. ECW Head to Head on June 7. At One Night Stand, Mysterio retained his title in a match after he and Sabu were ruled unable to continue following a triple jump DDT through a table from Sabu. Mysterio then retained his title against Mark Henry, winning by disqualification after Chavo Guerrero handed Henry a chair and Mysterio acted as if he was hit, thus Guerrero stole a trick from his uncle Eddie Guerrero.
Mysterio began a feud with King Booker after Booker won a battle royal to become the number one contender for the World Heavyweight Championship. Booker attacked Mysterio from behind backstage with the help of Booker's wife Queen Sharmell. The next week on SmackDown!, Mysterio gained revenge by attacking Booker and his "court". This rivalry continued for several weeks and saw Mysterio defeating Booker's court member William Regal on an episode of SmackDown!, moments before attacking the challenger and hitting him with a 619 around the steel post.
At The Great American Bash, Mysterio lost the World Heavyweight Championship after Chavo Guerrero turned on Mysterio and hit him with a steel chair, thus Chavo turned heel once again. Chavo cost Mysterio his rematch the following week. This culminated in a match at Summerslam where Mysterio lost to Guerrero after Vickie Guerrero tried to stop both men from fighting but accidentally knocked Mysterio off the top turnbuckle. Vickie then along with Chavo turned on Mysterio after she hit him in the back with a steel chair and gave him an injury, thus, siding with Guerrero. Mysterio then defeated Guerrero in a Falls Count Anywhere match at No Mercy. Subsequently Guerrero challenged Mysterio to an "I Quit" match. In that match, Chavo injured Mysterio's knee, using the match to write Mysterio out of the storyline for a while to get knee surgery.
Mysterio made his in-ring return at SummerSlam, defeating Guerrero with the 619, after Guerrero obsessed over Mysterio's return as well as wanting to injure Mysterio again.
On the August 31 episode of SmackDown!, Mysterio won a "Championship Competition" to become the number 1 contender for the World Heavyweight Championship, defeating Batista and Finlay. On the September 7 episode of SmackDown!, Mysterio had an "I Quit" match with Chavo Guerrero, which he won after hitting Guerrero's knee with a chair repeatedly in a similar manner to which Mysterio had been put out of action. Mysterio then began a feud with The Great Khali, which would lead to a match at Unforgiven where he would face Khali for the World Heavyweight Championship; the match was eventually made a Triple Threat match also involving Batista, but was unsuccessful in recapturing the title.
Mysterio then began a feud with Finlay, an opponent chosen by JBL. The rivalry was marked as "Fight vs. Flight", a competition between the two contrasting fighting styles of both wrestlers – Finlay's physicality, versus the high-flying Mysterio. On October 28, after fighting to a "no contest" at No Mercy, followed by a double-disqualification in a number one contender's match for Batista's World Heavyweight title on the next SmackDown! (The Undertaker would succeed the pair), he defeated Finlay in a Stretcher match at Cyber Sunday. During this feud, he conceded one match to Finlay on an episode of SmackDown! and was part of the winning team at Survivor Series which consisted of both wrestlers on opposing sides (although Mysterio was second to be eliminated).
He re-entered the world title picture when he emerged victorious in the Beat the Clock challenge for the chance to face the World Heavyweight Champion Edge at Royal Rumble. However, he was unsuccessful in winning the championship. WWE.com announced on February 14 that Mysterio suffered a biceps injury during an overseas tour. Despite the injury, Mysterio faced Edge for the title again at No Way Out. On the February 22 episode of SmackDown!, Mysterio announced that his injury would keep him out of action for at least six months, and he eventually underwent three surgeries within the space of a month.
Mysterio made his return on the June 23 episode of Raw, as Mysterio was the first wrestler to be drafted in the 2008 WWE Draft from the SmackDown brand to the Raw brand. On the June 30 episode of Raw, Mysterio came to make an announcement to all the Raw fans which led to a minor fight with Santino Marella. Mysterio made his Raw in-ring debut the next week, pinning Marella after a 619. General Manager Mike Adamle announced that John Cena was injured and that his replacement in the Championship Scramble at Unforgiven was Mysterio. The next week, Mysterio made his return to Raw after an extended absence by attacking Kane, turning back numerous claims that Kane had "ended his career". Mysterio then made his in-ring return at Unforgiven, competing in the Raw Championship scramble match. Mysterio began a feud with Kane next which lasted until Survivor Series. Kane called Mysterio a coward who hides behind a mask. As a result, Mysterio put his mask on the line against Kane at No Mercy, Mysterio won the match via disqualification after Kane hit Mysterio with a steel chair. Kane and Mysterio were once again booked in a No Holds Barred match at Cyber Sunday, Mysterio defeated Kane. The next night on Raw, Mysterio faced off against Evan Bourne in which Mysterio became victorious. After the match, he and Bourne were attacked by Kane and Mark Henry. Few weeks later, Rey Mysterio teamed up with Kofi Kingston in a losing effort against Kane and Henry, Kane once again made an attempt to attack Mysterio but he was saved by The Great Khali. At Survivor Series 2008, Team HBK which consisted of Shawn Michaels (the team captain), Rey Mysterio, The Great Khali and Cryme Tyme (JTG & Shad) defeated Team JBL (John Bradshaw Layfield, Kane, Montel Vontavious Porter, John Morrison & The Miz), thus ending the feud between Kane and Mysterio. He would shortly participate in an Intercontinental Championship tournament to determine the No.1 Contender for the William Regal's championship. Mysterio defeated The Miz and Kofi Kingston to advance to the finals of the tournament but ended up losing to CM Punk at Armageddon. Mysterio participated in the 2009 Royal Rumble match where he entered at No.1. He spent 49 minutes and 24 seconds in the match before being eliminated by the No.30 and final entrant Big Show. He qualified for Elimination Chamber spot the next night for the World Heavyweight Championship. He started at the No.1 position and survived to the final two before being eliminated by the winner Edge who attacked the original participant Kofi Kingston before and replaced him. Later, Mysterio accepted John "Bradshaw" Layfield's (JBL) challenge for Layfield's Intercontinental Championship at WrestleMania XXV, which Mysterio won in 21 seconds. With this win, Mysterio became the twenty first Triple Crown Champion in WWE history.
Mysterio was drafted back to SmackDown! during the 2009 WWE Draft on the April 13 episode of Raw, in the process making the Intercontinental Title exclusive to SmackDown for the first time since mid-2002.
He then began a long-time feud with Chris Jericho, resulting in Mysterio defending and retaining his title at Judgment Day. At Extreme Rules, Jericho managed to unmask Mysterio and pin him for the Intercontinental Championship, however his face was never shown, as he covered it. As a result, Mysterio and Jericho were booked in a Title vs. Mask match at The Bash, in which Mysterio was victorious after tricking Jericho with a second mask. On the July 10, episode of Smackdown, following a successful title defense against Chris Jericho, Mysterio was attacked by Dolph Ziggler. This began a rivalry between the two which culminated in a title match at Night of Champions where Mysterio retained. Mysterio once again defeated Ziggler to retain the Intercontinental title at Summerslam. On August 2, WWE announced that Mysterio would be suspended for 30 days, effective September 2, for violating the company's Wellness Policy. On the September 4 episode of SmackDown (taped on September 1), Mysterio lost the Intercontinental Championship to John Morrison.
Mysterio returned from his suspension at Hell in a Cell to face Jeri-Show (Chris Jericho and Big Show) for the Unified Tag Team Championships with former tag team partner Batista, but they failed to win the title after Mysterio was pinned by Big Show. At WWE Bragging Rights, Mysterio was unsuccessful in winning the World Heavyweight Championship in a Fatal Four-Way match including Batista, CM Punk, and then-champion The Undertaker. During the match, Mysterio broke up Batista's pin on Undertaker possibly costing him the match and the title. After the match, Batista turned heel by attacking Mysterio. Mysterio faced Batista at Survivor Series where Batista delivered three Batista Bombs on Mysterio leading to the referee stopping the match. Mysterio was defeated by Batista again in a street fight on the 11th December episode of SmackDown. A few weeks later Mysterio defeated Batista to be named the #1 Contender for the World Heavyweight Championship. Mysterio's title match against The Undertaker ended as a no-contest after interference from Batista. On January 1, 2010 Mysterio participated in a Beat the Clock Tournament for the #1 contendership of The Undertaker's World Heavyweight Championship at Royal Rumble. In the tournament, he defeated his former rival Chris Jericho, beating CM Punk's time. During Batista's "Beat the Clock" challenge against R-Truth, Batista was about to beat Mysterio's time, but Mysterio pulled the referee out of the ring during a pinfall as time ran out, costing Batista the tournament. Later it was announced that Mysterio and Batista would face each other the following week to decide the Number #1 Contender. However, this match also ended in a no-contest, following interference from the Undertaker. The following week in a rematch, Mysterio managed to win the title shot for the championship by defeating Batista in a Steel Cage match. At the Royal Rumble, The Undertaker successfully defended the championship against Mysterio.
Following the Rumble, Mysterio qualified for an Elimination Chamber match for the World Heavyweight Championship at the Elimination Chamber pay-per-view. In the weeks leading up to the Elimination Chamber, Mysterio began a feud with CM Punk that also involved Punk's Straight Edge Society. During the Elimination Chamber match, Mysterio eliminated Punk, but was ultimately eliminated by John Morrison. In the weeks following the Elimination Chamber event, Mysterio would continue to get the better of CM Punk, costing him a Money in the Bank qualifying match and defeating SES member Luke Gallows. During the on-screen celebration of Mysterio's daughter's ninth birthday, Punk interrupted, taunting Mysterio and challenging him to a match at WrestleMania XXVI. Mysterio later accepted the challenge. Punk later added the stipulation that if Mysterio were to lose at WrestleMania, he would be forced to join the SES. However Mysterio defeated Punk at WrestleMania. Five days later on SmackDown, Punk challenged Mysterio to another match at Extreme Rules, with the stipulation that if Mysterio won, Punk would have his head shaved bald. At Extreme Rules, Mysterio lost to Punk. At Over the Limit, Mysterio faced CM Punk again with both previous stipulations in place (Mysterio's allegiance to The SES vs Punk's hair.) Mysterio defeated Punk, resulting in Punk's hair being shaved.
On the May 28 episode of SmackDown, Mysterio fought The Undertaker unsuccessfully, to qualify for the World Heavyweight Championship title match at Fatal 4-Way but in the process, accidentally injured the Undertaker and took him out of the competition. On June 4, 2010, Mysterio won a Battle Royal involving the whole SmackDown roster by lastly eliminating Kane to earn The Undertaker's vacated spot, joining then-champion Jack Swagger, Big Show, and CM Punk at the pay-per-view. At Fatal 4 Way, Mysterio defeated Big Show, CM Punk and Jack Swagger to win the World Heavyweight Championship for the second time in his career. For the next month, Swagger continuously assaulted Mysterio using his ankle lock. At Money in the Bank, Mysterio defeated Swagger to retain the World title, however Swagger continued attacking the ankle after the match until Kane, who had earlier won the SmackDown Money in the Bank ladder match, came to the ring to chase Swagger away, seemingly to protect Mysterio. However, Kane returned with a referee and cashed in his title shot, quickly defeating Mysterio to win the World Heavyweight Championship. On the July 20 episode of SmackDown, Mysterio defeated Swagger in a 2 out of 3 falls match to remain the number one contender for the World Heavyweight Championship, earning a title match against Kane at SummerSlam. However, during the weeks before SummerSlam, Kane had marked Mysterio as the one who had attacked The Undertaker putting him in a vegetative state (which was a storyline put in place to explain Undertaker's absence due to the injury he had sustained against Mysterio in the Fatal Four Way qualifying match). Mysterio retaliated by saying that Kane was the true culprit. After the match at SummerSlam, which Mysterio ultimately lost, Kane had attempted to put Mysterio in a casket, only for The Undertaker to emerge from the casket. Mysterio ended up clearing his name The Undertaker revealed Kane to be the real attacker.
On the August 20 episode of SmackDown, he lost via submission to the debuting Alberto Del Rio. On the August 27 episode of SmackDown, Mysterio lost a No Disqualification match to Kane, and afterwards was attacked by Alberto Del Rio on his injured left arm, sparking a feud between the two. Mysterio returned on the first episode of SmackDown on Syfy and confronted Alberto Del Rio. After Del Rio escaped the ring, he hit his personal ring announcer with a 619. On the October 8 episode of SmackDown, Mysterio defeated Del Rio, and thus ending his undefeated streak. At Bragging Rights, Mysterio represented Team SmackDown, and despite an attack by teammate Del Rio, he and Edge managed to defeat the rest of Team Raw, giving Team SmackDown the victory. At Survivor Series, Mysterio led a team consisting of himself, Big Show, Chris Masters, MVP and Kofi Kingston to defeat Team Del Rio (Del Rio, Tyler Reks, Drew McIntyre, Jack Swagger, and Cody Rhodes). At TLC: Tables, Ladders & Chairs (2010), Mysterio participated in a fatal four way match for the World Heavyweight title against Kane, Edge and Del Rio, in a losing effort as Edge won the match to become the new champion. Mysterio would continue his feud with Del Rio which culminated on the January 7, 2011 episode of SmackDown in a 2 out of 3 falls match, which Del Rio ultimately won by countout due to interference from his personal ring announcer, Ricardo Rodriguez, ending the feud.
On the January 21 episode of SmackDown, Mysterio defeated Cody Rhodes. During the match, he broke Rhodes' nose when he hit Rhodes with a 619 with his exposed knee brace, thus sparking a feud. Mysterio participated in the Royal Rumble match at the Royal Rumble, though he was eliminated by Wade Barrett. The match would later be won by his rival, Alberto Del Rio. Five days later on SmackDown, Mysterio qualified for a spot in the Elimination Chamber match at the Elimination Chamber pay-per-view for the World Heavyweight Championship by defeating Jack Swagger. At the event he made it to the final two but was eliminated by Edge. On the February 25 episode of SmackDown, Mysterio was tricked and attacked by Cody Rhodes and his father, Dusty Rhodes, resulting in Mysterio being unmasked by Rhodes. At WrestleMania XXVII, Mysterio was defeated by Rhodes in a singles match. Mysterio would defeat Rhodes in a rematch on the April 23 edition of Smackdown and at Extreme Rules in a Falls Count Anywhere match to end the feud.
In the 2011 WWE Draft, Mysterio was drafted back to Raw. On the May 9 episode of Raw, Mysterio lost a Triple Threat match to determine the number one contender for the WWE Championship. Following the match, Mysterio was attacked by R-Truth which led to a match between the two at Over the Limit, which R-Truth won. From May, Rey Mysterio started feuding with CM Punk, with the pair exchanging victories on successive episodes of Raw. Their feud ended at WWE Capitol Punishment when Punk beat Mysterio. Rey Mysterio failed to capture the Raw Money In The Bank briefcase, eventually the match was won by Alberto Del Rio by unmasking Mysterio as a distraction. Mysterio advanced to the finals of a one night tournament on the July 18 episode of Raw, which culminated into a match between The Miz and Mysterio for the WWE Championship. The following week, Mysterio defeated Miz to win his first ever WWE Championship, nine years to the day of his WWE debut, also becoming a three-time world champion. Later that night, John Cena defeated Mysterio to become The Undisputed WWE Champion. On the August 8, 2011 episode of Raw, Mysterio was brutally attacked by The Miz, leaving him with a storylined injury. At SummerSlam 2011, Mysterio competed in a six man tag-team match with Kofi Kingston and John Morrison to defeat The Miz, Alberto Del Rio and R-Truth. The following night on Raw, Rey Mysterio received a rematch for the WWE Championship against new champion Del Rio, however Del Rio would retain.
Mysterio suffered an in-ring injury at a house show. Thereafter, it was put in a storyline injury inflicted by Alberto Del Rio following a match in August 2011, which would write Mysterio off television for about 10 months.
Rey Mysterio returned at the Slammy Awards to present the Superstar of the Year Award to CM Punk. Due to injury, Punk's award was accepted by Interim Raw GM John Laurinaitis. On April 26, 2012, WWE reported that Mysterio had been suspended for 60 days due to his second violation of the company's Talent Wellness Program policy and that his suspension would expire on June 25.
After almost a year's absence, Mysterio returned on the July 16 episode of Raw, saving Zack Ryder from his old rival, Alberto Del Rio. Four days later on SmackDown, Mysterio returned to in-ring action when he teamed up with World Heavyweight Champion Sheamus to defeat Del Rio and Dolph Ziggler via disqualification. At SummerSlam, Mysterio unsuccessfully challenged The Miz for the Intercontinental Championship. During the match, Mysterio suffered a legitimate concussion. He returned on the August 31 edition of Smackdown, defeating Cody Rhodes. At Night Of Champions, Mysterio failed again to capture the Intercontinental Championship from The Miz in a fatal-four way match, also involving Cody Rhodes and Sin Cara. The following day on Raw, Sin Cara and Mysterio teamed up to defeat Epico and Primo in a tag team match, after which they were attacked by the Prime Time Players (Darren Young and Titus O'Neil). On the October 1 episode of Raw, Sin Cara and Mysterio entered a tournament to determine the number one contenders to the WWE Tag Team Championship, defeating Epico and Primo in their first round match. A week later, Mysterio and Sin Cara defeated the Prime Time Players to advance to the finals of the tournament. Mysterio and Sin Cara were set to face the team of Cody Rhodes and Damien Sandow on the October 15 edition of Raw, but the match was postponed due to Mysterio legitimately suffering from effects of the stomach flu. Mysterio returned on the October 22 episode of Raw, where he and Sin Cara were defeated in the finals of the tournament by Rhodes and Sandow. At the Survivor Series pay-per-view, Mysterio and Sin Cara were victorious in a 10 man elimination tag team match alongside Tyson Kidd, Justin Gabriel and Brodus Clay against Titus O' Neil, Darren Young, Primo, Epico, and Tensai. Mysterio and Sin Cara challenged Team Rhodes Scholars once more for #1 contendership to the WWE Tag Team Championship at the 2012 TLC pay-per-view event, but were unsuccessful. After a few days, when Rey was to accompany Sin Cara to a match, he couldn't come, as he was ambushed backstage by The Shield. This was used as a storyline to write them off television as he was taking some time off, and Sin Cara underwent a knee surgery.
Mysterio returned as the fourteenth participant in the 2013 Royal Rumble match on January 27th, 2013. However, he didn't manage to eliminate anyone and Mysterio was elimated by Wade Barrett as number 13, before his tag team partner Sin Cara entered. He returned to teaming with Sin Cara on the February 1st edition of SmackDown, defeating WWE Tag Team Champions Team Hell No. The next week on Raw, he was attacked by the returning Mark Henry. Rey Mysterio returned at a WWE Live Event on September 22 in Hidalgo,TX. Mysterio came out on a crutch, and made a quick appearance in front of fans to announce that he will be returning to action on October 16th when WWE kicks off its tour of Mexico.
Mysterio made his televised return at the Hell in a Cell 2013 PPV as part of the Spanish announce team.
On the November 18th Country edition of Raw, Rey Mysterio returned and helped CM Punk and Daniel Bryan. He also did the "619" on both Jack Swagger and Luke Harper. This was continued with a GTS by CM Punk and the running knee by Daniel Bryan. It was later announced that Mysterio would team up with Cody Rhodes, Goldust and The Usos against The Shield and The Real Americans in a 10 man elimination tag team match at Survivor Series. On the 22nd of November episode of Smackdown, Rey Mysterio and The Usos defeated The Shield with Mysterio pinning Dean Ambrose. At TLC: Tables, Ladders and Chairs Mysterio teamed with Big Show to unsuccessfully challenge Cody Rhodes and Goldust for the WWE Tag Team Championship in a four-way match, also involving Ryback and Curtis Axel, and The Real Americans. At the Royal Rumble pay-per-view on January 26, 2014, Mysterio entered the Royal Rumble match at #30, but was eliminated by Seth Rollins. At WrestleMania XXX, Mysterio competed in the André the Giant Memorial Battle Royal but was eliminated by Cesaro. Mysterio faced Wade Barrett the next night, and was continuously booed by the predominately-British crowd. This proved to be his final appearance for WWE.
During his hiatus, it was reported that Mysterio wanted to leave WWE but that the promotion had extended his contract without his approval. On February 26, 2015, Mysterio's WWE contract expired, ending his 13-year tenure with the company.