During Raw's WrestleMania Revenge tour of Europe in April 2010, Del Rio made numerous appearances in untelevised matches for the Raw brand. One night he wrestled as Dos Caras, like his father before him. He was presented as a villain in a losing effort against Christian. The following month Del Rio put on a mask for WWE's tour of Mexico and worked as a hometown hero, prior to returning unmasked during untelevised matches for subsequent Raw and SmackDown shows.
On the June 25, 2010 episode of SmackDown, Del Rio debuted on a pre-taped promotional video. Thereafter, a vignette aired every week on SmackDown promoting his character as an arrogant rich Mexican aristocrat, espousing his own virtues of honesty, integrity and mental faculties. After two months, he debuted on the August 20 episode of SmackDown by defeating fellow luchador Rey Mysterio in the main event using his new cross armbar submission. As part of his act, Del Rio maked his entrances in an expensive car, while being introduced by his personal ring announcer, Ricardo Rodriguez. The following week, Del Rio continued the storyline with Mysterio by attacking him after his match with Kane, giving him a storyline injury by refusing to relinquish his armbar. Two weeks later he defeated Matt Hardy via submission in Hardy's last appearance with the company, causing Hardy's friend Christian to challenge Del Rio to a match at Night of Champions. Although he declined the match, on the September 24 episode of SmackDown Del Rio attacked Christian and injured him the same way he did Mysterio the previous month, marking the third successive wrestler Del Rio was scripted to injure. This was done to write Christian off television, as he had suffered a torn pectoral muscle. Mysterio returned on the October 8 SmackDown episode and handed Del Rio his first defeat in the main event match. In October Del Rio defeated Chris Masters to represent the SmackDown brand at Bragging Rights, but during the pay-per-view event he attacked teammate Rey Mysterio, before being eliminated from the match by Team Raw's CM Punk. At Survivor Series, in the traditional five-on-five elimination match, Del Rio captained a team against Rey Mysterio's team. Although Del Rio's team lost he was never technically eliminated, instead Big Show knocked him out with a punch and he was removed from the match. On the November 26 SmackDown, Del Rio defeated Big Show via countout to qualify for the 2010 King of the Ring tournament. In the tournament the next week on Raw, he made WWE United States Champion Daniel Bryan submit in the first round, but was defeated by John Morrison in the semi-final after being distracted by Mysterio, who was inside his car. On the November 30 episode of WWE NXT, it was announced that Del Rio would mentor Conor O'Brian on the fourth season of NXT, starting the following week. On December 19 at TLC: Tables, Ladders & Chairs Del Rio competed in a Fatal four-Way Tables, Ladders and Chairs match for the World Heavyweight Championship, which was won by Edge and also included then-champion Kane and Rey Mysterio. On the January 7, 2011 episode of SmackDown, Del Rio defeated Mysterio in a Two Out of Three Falls match, with help from Ricardo Rodriguez to end his long feud with Mysterio.
On January 18, 2011, Del Rio's NXT rookie Conor O'Brian became the second contestant eliminated from the competition. The following week the rookies competed in a Fatal Four Way match, of which the winner could change their pro. Brodus Clay won the match and chose Del Rio as his new pro. After the conclusion of NXT, Clay was hired as the bodyguard of Del Rio. On January 30, 2011, Del Rio defeated 39 other participants to win the 2011 Royal Rumble and earn the right to compete for either the World Heavyweight Championship or the WWE Championship at WrestleMania XXVII by last eliminating Santino Marella. The following night on Raw, Del Rio chose to compete for the World Heavyweight Championship, which, at the time of his choosing, was held by Edge. At Elimination Chamber, Del Rio attacked Edge, after he had successfully defended his World Heavyweight Championship and solidified his spot as Del Rio's opponent at WrestleMania. However, Edge managed to come out the exchange victorious, after Christian made a return from his injury and attacked Del Rio. On the March 18 episode of SmackDown, Del Rio and Christian finally had their first one–on–one match inside a steel cage, in which Christian was victorious. At WrestleMania XXVII, Del Rio was unsuccessful in his World Heavyweight Championship match against Edge. On the following episode of SmackDown, Del Rio defeated Christian to earn a rematch against Edge at Extreme Rules. However, when Edge unexpectedly announced his retirement from professional wrestling on the April 11 episode of Raw, Del Rio was instead booked to face Christian in a ladder match for the vacant World Heavyweight Championship.
On the April 25, 2011, episode of Raw, Del Rio was drafted from SmackDown to Raw. Ricardo Rodriguez moved to Raw with him, while Brodus Clay remained on SmackDown. On May 1 at Extreme Rules, Christian defeated Del Rio in a ladder match to win the vacant World Heavyweight Championship. On the May 23 episode of Raw, Del Rio slapped Big Show after he had gotten into a confrontation with Ricardo Rodriguez. After competing in a match, Show was run over by Del Rio's car, being driven by Rodriguez, leaving him sidelined with a storyline knee injury. Big Show made his return three weeks later, chasing Del Rio out of the ring and beating Rodriguez down. On June 19 at Capitol Punishment, Del Rio defeated Big Show via referee stoppage, when Show was unable to continue the match as a result of a pre-match assault by Mark Henry. On the June 27 episode of Raw, Del Rio defeated Big Show in a steel cage match, again with help from Mark Henry. On July 17 at Money in the Bank, Del Rio defeated Alex Riley, Evan Bourne, Jack Swagger, Kofi Kingston, The Miz, R-Truth and Rey Mysterio in a Money in the Bank ladder match to earn the right to challenge for the WWE Championship whenever and wherever he wanted, while also becoming the first wrestler in history to win a Royal Rumble and a Money in the Bank match in the same year. Following the orders of Vince McMahon, Del Rio attempted to cash in his contract later that same night on CM Punk, who had just defeated John Cena for the WWE Championship, but was attacked and laid out by him before he could do so. Del Rio eventually cashed in his contract on August 14 at SummerSlam, challenging CM Punk after the main event, where he had defeated John Cena to become the undisputed WWE Champion. Between the two matches, Punk was attacked by Kevin Nash, which led to Del Rio scoring a quick pinfall victory to win the WWE Championship for the first time. In winning the title, Del Rio became the first ever Mexican-born WWE Champion. Del Rio made his first televised title defense the following night on Raw, defeating Rey Mysterio to retain his title. On September 18 at Night of Champions, Del Rio lost the WWE Championship to John Cena. Del Rio regained the title on October 2 at Hell in a Cell by defeating Cena and CM Punk in a Hell in a Cell match. On October 23 at Vengeance, Del Rio successfully defended the WWE Championship against John Cena in a Last Man Standing match, following interference from The Miz and R-Truth. On November 20 at Survivor Series, Del Rio lost the WWE Championship to CM Punk. Del Rio received a rematch for the WWE Championship on the November 28 episode of Raw, but was defeated after CM Punk dropped him onto an exposed turnbuckle, managing to avoid a disqualification, which would have cost him the title, in the process. On December 18 at TLC: Tables, Ladders & Chairs, Del Rio failed again to recapture the WWE Championship from CM Punk in a Triple Threat Tables, Ladders, and Chairs match, also involving The Miz. The following night on Raw, Del Rio suffered a torn groin muscle, which required surgery and sidelined him for four to six weeks.
Del Rio made his return at a WWE house show in San Francisco on February 11, 2012, arm wrestling Sheamus to a no contest. On February 19 at Elimination Chamber, Del Rio made an appearance to show support to Raw General Manager John Laurinaitis. Del Rio returned on the April 2 episode of Raw, confronting World Heavyweight Champion Sheamus and vowing to become the next champion. On the following episode of SmackDown, Del Rio defeated Sheamus in a non-title match via disqualification to earn a shot at the World Heavyweight Championship. On the April 20 episode of SmackDown, it was announced that Del Rio and Ricardo Rodriguez had been officially traded from Raw to SmackDown. On May 20 at Over the Limit, Del Rio failed to capture the World Heavyweight Championship from Sheamus in a Fatal Four-Way match, also involving Chris Jericho and Randy Orton. On the following episode of SmackDown, Del Rio defeated Kane and Randy Orton in a Triple Threat match to become the number one contender to the World Heavyweight Championship. At the June 5 tapings of SmackDown, Del Rio suffered a legitimate concussion, which led to WWE pulling him from his scheduled World Heavyweight Championship match against Sheamus at No Way Out. Del Rio returned on the June 18 episode of Raw, defeating United States Champion Santino Marella in a non-title match. The following week on Raw, Del Rio wrestled Dolph Ziggler to a no contest in a Contract on a Pole match for a shot at the World Heavyweight Championship. As a result, both Del Rio and Ziggler were entered into the championship match four days later on SmackDown, where Sheamus retained the title after pinning Ziggler. Del Rio received another shot at the World Heavyweight Championship on July 15 at Money in the Bank, where he was again defeated by Sheamus. The following night on Raw, Del Rio was looking to take out his frustrations on Zack Ryder, but his post-match assault was interrupted by his longtime rival Rey Mysterio making his return and attacking him. Four days later on SmackDown, Del Rio and Dolph Ziggler were defeated by Mysterio and Sheamus via disqualification, following interference from Rodriguez. After the match, Del Rio viciously attacked Sheamus. On the July 27 episode of SmackDown, Del Rio defeated Daniel Bryan, Kane, and Rey Mysterio in a four-way match to again become number one contender for the World Heavyweight Championship. The title match, originally announced for SummerSlam, was moved to the August 10 episode of SmackDown, after Del Rio threatened to press charges against Sheamus for stealing his car on the previous episode of Raw, which would have prevented Sheamus from appearing at the pay-per-view. However, before the match got started, Del Rio attacked Sheamus along with men posing as police officers, which led to SmackDown General Manager Booker T taking away his number one contender's status as a result. However, the following week, Sheamus had the title match put back on for SummerSlam. At the pay-per-view on August 19, Del Rio again failed in attempt to dethrone Sheamus after the referee failed to notice Del Rio's foot on the bottom rope. On the following episode of SmackDown, Del Rio defeated Randy Orton via submission to once again become the number one contender for the World Heavyweight Championship. On the September 7 episode of SmackDown, Del Rio filed assault charges against Sheamus, after Sheamus had attacked him and Rodriguez on the previous Raw, which led to Booker T banning the Brogue Kick with the caveat that Sheamus would be stripped of the World Heavyweight Championship if he used the move again. However, on September 16 at Night of Champions, Booker T announced that he had concluded his investigation into the dangers of the move and lifted the ban. In the match that followed, Sheamus used the Brogue Kick to defeat Del Rio and retain the World Heavyweight Championship.
With his rivalry with Sheamus behind him, Del Rio moved on to feuding with Randy Orton, with the two attacking each other on the September 28 episode of SmackDown. The rivalry built to a singles match on October 28 at Hell in a Cell, where Orton emerged victorious. On the following episode of Main Event, Del Rio teamed with The Prime Time Players (Darren Young and Titus O'Neil) to face Orton and the team of Rey Mysterio and Sin Cara in six-man tag team bout that ended with Orton pinning Del Rio for the win. On the November 6 episode of SmackDown, Del Rio was again defeated by Orton in a Falls Count Anywhere Match, after taking an RKO onto the ringside steel steps. The two were then on opposing teams for the traditional five-on-five elimination tag match on November 18 at Survivor Series. Del Rio's team, led by Dolph Ziggler, ended up defeating Orton's team, led by Mick Foley, despite Del Rio being eliminated by Orton prior to the finish. The following night on Raw, Del Rio was once again defeated by Orton in a Two Out of Three Falls match, ending the feud.
On December 16 at TLC: Tables, Ladders & Chairs, Del Rio turned face for the first time in his WWE career, when he saved Ricardo Rodriguez and the Spanish announce team from 3MB (Drew McIntyre, Heath Slater, and Jinder Mahal). Later in the event, Del Rio teamed with The Miz and The Brooklyn Brawler to defeat 3MB in a six-man tag team match. The following night on Raw, Del Rio and Miz teamed up with Tommy Dreamer to defeat 3MB in another six-man tag team match. On the December 28 episode of SmackDown, Ricardo Rodriguez was awarded a title match against World Heavyweight Champion Big Show, but Show knocked Rodriguez out backstage. Del Rio was then awarded the title match in Rodriguez's place, however, the match ended in a no contest after Sheamus attacked Big Show. On the December 31 episode of Raw, Show chose to defend his title against Rodriguez. As Rodriguez was about to lose the match, Del Rio attacked Show from behind, causing a disqualification and re-igniting a feud between Del Rio and Show. On January 8, 2013, at the tapings of the January 11 episode of SmackDown, as Del Rio's character transitioned into a hero of the Latino fanbase, he defeated Show in a Last Man Standing match to win his first World Heavyweight Championship. Del Rio made his first successful title defense on January 27 at the Royal Rumble, defeating Show in another Last Man Standing match, after Rodriguez duct taped Show's legs to the ropes. After repeated attacks from Show to both himself and Rodriguez, Del Rio and Show faced off in a singles match on February 17 at Elimination Chamber, where Del Rio submitted him to the Cross Armbreaker to retain his title. Del Rio then began a feud with his new number one contender, Jack Swagger, over his opposing political views regarding immigration in America. The feud escalated on the March 18 episode of Raw, when Swagger broke Rodriguez's ankle with his Patriot Act submission. Del Rio continued his feud with Swagger on the April 1 episode of Raw, defeating Swagger's manager Zeb Colter via disqualification after Colter hit Del Rio with Ricardo Rodriguez's crutch. On April 7 at WrestleMania 29, Del Rio defeated Swagger via submission to retain the World Heavyweight Championship. The following night on Raw, Del Rio defeated Swagger and Zeb Colter in a Two-on-one handicap match after forcing Swagger to submit to the Cross Armbreaker. Immediately following, Del Rio lost the World Heavyweight Championship to Dolph Ziggler who cashed in his Money in the Bank briefcase, ending his reign at 90 days. Following the loss of the World Heavyweight Championship, Del Rio would continue feud with Swagger and Ziggler over the title. On the April 29 episode of Raw, Ricardo Rodriguez defeated Big E Langston and Zeb Colter in a three-way match to give Del Rio the right to choose the stipulation of his three-way match at Extreme Rules and chose a ladder match. However, Ziggler would suffer a legitimate concussion at a SmackDown taping, thus removing their match from Extreme Rules. As a result of Ziggler's injury, Del Rio instead would be booked to face Swagger in a number one contender I Quit match at the pay-per-view on May 19, which Del Rio won. In the following weeks, Del Rio would face Ziggler's associate Big E Langston in a series of matches, with the two trading victories over one another on Raw, Main Event, and SmackDown.
At Payback, Del Rio defeated Ziggler to regain the World Heavyweight Championship. However, he also showed signs of a heel turn. During the match, Del Rio heavily targeted Ziggler's head, where Ziggler had just recovered from a recent legitmate concussion. During the match, a rare double turn took place when Del Rio turned heel by targeting Ziggler's head after his recent concussion. Del Rio explained the next night on Raw that he targeted Ziggler's head the same way Ziggler targeted Del Rio's injured leg when he cashed in his Money in the Bank Briefcase, and accosted the fans who cheered for Ziggler, thus turning heel for the second time in his career.
On July 14 at Money in the Bank, Del Rio defeated Ziggler via disqualification to retain the World Heavyweight Championship, after Ziggler's girlfriend AJ Lee hit Del Rio in the face with her Divas Championship belt. The following night on Raw, Del Rio defeated Ziggler in a non-title rematch after a distraction by AJ. On the July 29 episode of Raw, Del Rio re-entered a feud with Christian after losing to him in a non-title match. That same week on SmackDown, after Christian won a three-way match against to become the number on contender to the World Heavyweight Championship, Del Rio attacked him during a post-match interview. On the following episode of Raw, Del Rio lost a non-title match to Rob Van Dam, after Ricardo Rodriguez's interference backfired, which led to Del Rio viciously attacking Rodriguez post-match. Four days later on SmackDown, Del Rio was again defeated by Christian in a non-title match. On August 18 at SummerSlam, Del Rio successfully defended the World Heavyweight Championship against Christian. The following night on Raw, Ricardo returned and announced to Del Rio that he now represents Rob Van Dam. On the September 13 episode of SmackDown, Del Rio defeated Rodriguez in a single match. Two days later at Night of Champions, Del Rio and Van Dam's title match ended in a disqualification win for Van Dam, after Del Rio refused to relinquish the Cross Armbreaker, retaining the World Heavyweight Championship as a result. After the match, Van Dam attacked Del Rio and hit him with the Van Terminator. On October 6 at WWE Battleground, Del Rio defeated Van Dam in a Hardcore match via submission to again retain his title. On October 7, Del Rio was defeated by Ricardo Rodriguez. It was announced by Smackdown! GM Vickie Guerrero that Del Rio would be facing John Cena for the World Heavyweight Championship at Hell In a Cell. At Hell In a Cell, Del Rio lost his championship to John Cena, ending his reign at 133 days. Del Rio received his rematch for the title on November 24 at Survivor Series, but was again defeated by Cena.
On the December 2 and 9 episodes of Raw, Del Rio suffered upset losses to the returning Sin Cara. Del Rio finally defeated Sin Cara on the January 6, 2014, episode of Raw. After the match, Del Rio insulted the soon-to-be returning Batista and that he would eliminate Batista in the Royal Rumble to get everyone talking about him. On the January 13 episode of Raw, he defeated Rey Mysterio and after the match , once again confronted Batista. On the January 20 episode of Raw, after he defeated Rey Mysterio, Batista returned and attacked Del Rio with a Batista Bomb. Six days later at the Royal Rumble, Del Rio entered the Rumble match at number 27 and performed well, but was eliminated Batista who went on to win the match. On the February 3 episode of Raw, Del Rio confronted and ultimately assaulted Batista, which led to Batista powerbombing Del Rio through the announce table the following week. Before that, Del Rio squashed Dolph Ziggler. This led to a match between Del Rio and Batista at Elimination Chamber, which Batista won. The following night on Raw, Del Rio defeated Batista in a rematch from the previous night. On June 2 episode of Raw, Del Rio defeated Dolph Ziggler to qualify for the 2014 Money in the Bank ladder match. However, he would be defeated in the Money In The Bank ladder match itself against Randy Orton, Sheamus, Kane, Bray Wyatt, Roman Reigns, Cesaro and winner John Cena. Five days later, on Independence Day Smackdown, he challenged Sheamus for the United States Championship but failed to do so. He then defeated Dolph Ziggler on the July 7 Raw to earn another United States Championship opportunity against Sheamus but lost a Last Man Standing match the following night on Main Event. At Battleground, Del Rio participated in the Intercontinental Championship Battle Royal, but was eliminated by Dolph Ziggler. On the August 5 episode of Main Event, Del Rio was defeated by Jack Swagger in what would be his final match as he was released thereafter.
On August 7, 2014 WWE released Del Rio from the company due to "unprofessional conduct" and an altercation with an employee.
Del Rio made an unannounced return to WWE at Hell in a Cell on October 25, 2015 as a heel. With Zeb Colter as his manager, he defeated John Cena to win the WWE United States Championship for the first time. The next night on Raw, Del Rio revealed he and Zeb Colter had started their new country "MexAmerica" and unofficially renamed the United States Championship as the "MexAmerica Championship". In November, a tournament was announced for the vacant WWE World Heavyweight Championship, which Del Rio took part of, defeating Stardust in the first round and Kalisto in the quarterfinals. He, however, would lose in the semifinals to Roman Reigns at Survivor Series.
On the November 23 edition of Raw, Del Rio and Colter put an end to MexAmerica, saying Americans had their chance to join them but they were all too busy being selfish and hateful. Del Rio was then interrupted by Jack Swagger before losing to Swagger on the November 26 episode of SmackDown via disqualification when Del Rio attacked Swagger with a steel chair. On the November 31 edition of Raw Del Rio defeated Goldust and would then go on to apply the cross arm breaker on Goldust after the match until Jack Swagger made the save. Later in the night Del Rio was revealed as a member of the new stable the League of Nations. Del Rio, representing Mexico was joined by Ireland's WWE World Heavyweight Champion Sheamus, England's King Barrett, and Bulgaria's Rusev. In the main event, The League of Nations defeated the team of Roman Reigns, Dean Ambrose and The Usos. On the next week's Raw, Del Rio ended his alliance with Zeb Colter, stating that he "didn't need him anymore". At the TLC: Tables, Ladders and Chairs pay-per-view, Del Rio retained the United States Championship against Jack Swagger in a chairs match. Del Rio reignited his feud with John Cena, after the latter returned on December 28. On that episode of Raw, Cena challenged Del Rio to a US Title match, which Del Rio accepted. Del Rio would lose the match by disqualification due to interference from his fellow League of Nations members, but kept the title. On the January 7, 2016 episode of SmackDown, Del Rio lost a non-title match to Kalisto, therefore giving Kalisto a future title opportunity. Kalisto received that shot four days later on Raw, where he beat Del Rio to win the United States Championship, ending Del Rio's reign at 78 days. He, however, won the title back just three days later on WWE SmackDown, following an assist from King Barrett. He would lose the title to Kalisto again on January 24 at Royal Rumble. Later on, in the Royal Rumble Match, Del Rio injured his back after taking numerous suplexes from Brock Lesnar, deeming him out of action for the following week. Del Rio returned to action teaming with Rusev on a February 2nd SmackDown taping losing to Roman Reigns and Dean Ambrose. Del Rio used his rematch clause in a 2-out-of-3-falls match at Fastlane. Del Rio would lose the first fall by disqualification and win the second fall. However, Del Rio would lose the third fall resulting in him losing the match.
At WrestleMania 32, Del Rio was part of a 4 on 3 tag match along with his fellow League of Nations members King Barrett, Sheamus and Rusev, against The New Day, where his team won when Sheamus pinned Xavier Woods. After WrestleMania, The League of Nations began to dissolve when King Barrett was ejected from the group on the April 4 Raw, where Del Rio and the rest of the group attacked him. On the April 28 edition of SmackDown, the group officially disbanded after Del Rio and Rusev walked out on Sheamus during a six-man tag match against Sami Zayn, Kalisto, and Cesaro.
On the May 2 episode of Raw, Del Rio was involved in a Battle Royal to determine the #1 contender for Kalisto's United States Championship, but was eliminated by Zack Ryder. On the May 26 episode of SmackDown, Del Rio defeated Zack Ryder to qualify for the 2016 Money in the Bank ladder match. At the event, Del Rio was unsuccessful as the match was won by Dean Ambrose. On July 19, at the 2016 WWE Draft, Del Rio was drafted to SmackDown.
On August 17, 2016, Del Rio was suspended for thirty days for his first violation of WWE's wellness policy. On September 9, WWE officially announced that they had come to terms with his release from the company.