Chavo made his WWF debut in 2001 as part of The Alliance.
Guerrero spent time as an undercard wrestler in the company, which was soon rebranded World Wrestling Entertainment, before becoming a trainer for WWE's second Tough Enough competition. Soon after returning to the active roster, Guerrero was aligned with his uncle Eddie, forming the tag team Los Guerreros. Guerrero fully adopted his uncle's policy of "Lie, Cheat and Steal" to win matches as part of the gimmick. The duo won the WWE Tag Team Championship twice, feuding with such teams as Edge and Rey Mysterio and Team Angle.
The tag team eventually turned into fan favorites and as Eddie's popularity grew, he began seeking the WWE Championship. In one angle, his uncle's singles title ambitions made Guerrero jealous and Guerrero turned on Eddie, broke from the team, and became a villain again. He was soon joined by his father Chavo Sr. who sided with his son instead of his brother. Eddie defeated Chavo at the 2004 Royal Rumble.
After the feud with Eddie finished, Guerrero became a wrestler in the cruiserweight division and captured the WWE Cruiserweight Championship on several occasions.
On February 15, 2004, at a Smackdown-exclusive No Way Out in Daly City, California, Chavo, with his father, Chavo Classic, in his corner, defeated Rey Mysterio to win the WWE Cruiserweight Title. On a May 4 taping of Smackdown! in Tucson, Arizona, Chavo would eventually drop the title to returning WWE Diva Jacqueline after he issued an open challenge for anyone to face him for his title. He would regain the title on May 16, 2004 at Judgment Day in a match with his hand tied behind his back, though his father Chavo Classic untied it during the match. Chavo again dropped the title on a May 18 taping of Smackdown! in Las Vegas, Nevada, this time to Chavo Classic, who "accidentally" pinned his son in a Triple Threat Match which involved Spike Dudley.
On an August 26, 2004 episode of SmackDown!, Guerrero suffered a legitimate concussion due to Billy Kidman's shooting star press and had to be taken to the hospital. Guerrero returned several months later as a fan favorite again, exacting revenge from Kidman, who had turned into a villain as a result of the injury to Guerrero, but shortly returned to his villainous persona after receiving a villain reaction after facing then-cruiserweight champion Funaki in a losing effort during a SmackDown! show in Japan.
Guerrero went on to become Cruiserweight Champion once again at No Way Out in 2005 after eliminating Paul London in a six-way cruiserweight gauntlet match. He would lose the title to London in a battle royal a few weeks later; Guerrero was the first person eliminated from the battle royal when everyone else in the match ganged up to throw him out right at the beginning. In reality, Guerrero was forced to drop the title due to a broken orbital bone that would sideline him for several weeks.
On June 30, Guerrero became one of the last minute trades in the 2005 WWE Draft, which saw him jump from SmackDown! to the Raw brand. The next week, on Raw, he denounced his Hispanic heritage in favor of the Anglo-American way. This came after two weeks of being battered by the Mexican faction, The Mexicools. It led to the changing of his persona to "Kerwin White", a stereotypical, middle-class, white, conservative, Anglo-American man. He dyed his hair blond and often drove a golf cart to the ring which held his golf clubs. His new catchphrase became the pun, "If it's not White, it's not right." The phrase later changed to "If it's not Kerwin White, it's not right". It was later phased out entirely. Soon after his debut, White started making suggestive remarks towards African Americans, Hispanics, Asian Americans, Native Americans, and other non-White people, specifically directed towards then-babyface, Shelton Benjamin. On an episode of Raw, White cost Shelton a match against Rob Conway. Benjamin defeated White by disqualification the following week when Kerwin attacked Shelton with his golf club At Unforgiven, White was beaten by Benjamin. White then hired Dolph Ziggler as his new "caddy" to help him in his matches.
On November 13, 2005, his uncle, Eddie died in his hotel room.
Later that afternoon, Guerrero appeared at a press conference with WWE Chairman Vince McMahon to address Eddie's death. They announced that both shows that week would be tributes to Eddie. These events resulted in Guerrero dropping the Kerwin White gimmick and wrestling under his real name as a fan favorite to continue the Guerrero legacy. Under his real name, he defeated John "Bradshaw" Layfield (JBL) on the November 18, 2005 episode of SmackDown!, using the "Three Amigos" triple suplexes and the Frog Splash in tribute to Eddie. He also used the cheating tactic of throwing a steel chair to an opponent who catches it (while laying down himself) as the referee turns around and disqualifies the opponent, which Eddie made famous.
On the February 24, 2006 episode of SmackDown!, Guerrero attacked Randy Orton with the Three Amigos and the frog splash when Orton began to insult Eddie, and talked about the heritage of the Guerreros. Guerrero was soon dragged out by security, but kept yelling to Orton "You forgot about the Guerreros - the greatest wrestling family!" and "You forgot me!". On the February 27 episode of Raw, Guerrero faced off against now-heel Shelton Benjamin in a qualifying match for the Money in the Bank ladder match at WrestleMania 22. During the match, Orton interfered and hit Guerrero with the RKO. This allowed Shelton to get the pinfall victory. On the April 3 episode of Raw, Guerrero came out to address the crowd. He thanked the fans for all the support they had given him and his family and for keeping Eddie's spirit alive, but he expressed his disappointment in not having a title match at WrestleMania 22. He felt that night would become his WrestleMania and he was going to dedicate his match to his Eddie. He proceeded to challenge Shelton Benjamin for the WWE Intercontinental Championship, but ended up losing after he missed a Frog Splash, allowing Benjamin to connect with his T-Bone Suplex finisher. In a segment that aired on WWE Unlimited, an emotional Guerrero decided to quit WWE, in storyline, after believing he had let his family, Eddie, and the fans down and expressed his doubts about being a wrestler.
On May 13, Guerrero appeared at a SmackDown! house show in El Paso, defeating then-heel Finlay. Guerrero also appeared at Judgment Day to support Rey Mysterio. Guerrero would then support Mysterio for a few weeks on SmackDown!. At the Great American Bash, Guerrero interfered in Mysterio's World Heavyweight Championship match, ostensibly to help Mysterio. Guerrero turned into a villain once more, however, by hitting Mysterio with a steel chair, which allowed challenger King Booker to win the match. On the August 4 episode of SmackDown!, Guerrero accused Rey of using Eddie's name to succeed, claiming that Rey disrespected Eddie's memory. Guerrero went on to beat Mysterio at SummerSlam, after Vickie Guerrero accidentally knocked Mysterio off the top turnbuckle. On August 25, Vickie came down to the ring to apologize to Mysterio and Guerrero. Vickie ended up turning on Mysterio by hitting him in the back with a steel chair. The following week on SmackDown!, Vickie announced herself as Guerrero's new manager. Weeks later on October 8, Mysterio gained his revenge on Guerrero by defeating him in a Falls Count Anywhere match at No Mercy. Guerrero eventually challenged Mysterio to an "I Quit" match, in which Guerrero won after inflicting multiple chair shots to Rey Mysterio. As per the condition of the match, Mysterio was forced to leave SmackDown!, possibly ending the emotional feud between the two.
A week later, Chris Benoit, another old friend of Eddie's, tried talking to Vickie, but she would not hear it. It started a feud between Guerrero and Benoit and both men would have numerous confrontations over the following weeks. Benoit defeated Guerrero to retain the WWE United States Championship at the Survivor Series. After weeks of continued interaction, the two faced off in a United States title rematch at Armageddon that Guerrero also lost when he tapped out to a Sharpshooter. Guerrero got yet another rematch the following Friday, losing the match after Vickie hit Benoit with the title belt. Guerrero snapped after the match, knocking over Vickie and attacking Benoit. The feud concluded with Benoit forcing Guerrero to submit in a No Disqualification match.
At No Way Out, Guerrero was labeled a surprise entrant in a Cruiserweight Open Match by the announcers (despite already having been advertised as one of the wrestlers in the match on WWE.com and on the No Way Out merchandise); he entered last and pinned Jimmy Wang Yang after a frog splash, thus winning the Cruiserweight Championship from Gregory Helms. On June 24, Guerrero retained his title against Jimmy Wang Yang at Vengeance: Night of Champions. He then retained his title on the June 29 episode of SmackDown! in a triple threat match that also involved Jamie Noble and Funaki, when he pinned Funaki after the Gory Bomb. At The Great American Bash, he lost the Cruiserweight title in a Cruiserweight open when Hornswoggle pinned Noble (Hornswoggle was not originally in the match but was in the ring when the bell rang, thus becoming an official entrant).
Guerrero then turned his attention to Rey Mysterio, whom he had put out of action, in storyline, in 2006. Before Mysterio's return at SummerSlam, Guerrero mocked Mysterio's knee injury and taunted him during matches. He was, however, unable to defeat Mysterio at the pay-per-view. He then lost an "I Quit" rematch to Mysterio, when Mysterio continued to assault Chavo's left knee with a steel chair, which is what Chavo did to Mysterio in the first "I Quit" match thus injuring him in storyline. This allowed Guerrero to have time off to serve his suspension for violating the WWE Wellness Policy.
Chavo remained inactive until the December 18, 2007 episode of ECW, where he appeared after the main event between WWE United States Champion Montel Vontavious Porter and ECW Champion CM Punk and proceeded to attack the vulnerable ECW Champion, sending a message that he wanted a title shot.
With the beginning of 2008, Guerrero entered a feud with CM Punk regarding his ECW title. Guerrero challenged Punk to several matches until he finally won the third via countout after interference from World Heavyweight Champion Edge to earn a championship match. The previous matches he lost via countout and disqualification. On the January 22 episode of ECW, Guerrero defeated CM Punk in a No Disqualification match to win the ECW Championship following interference from Edge. In the process he proclaimed Edge and company as his "familia". He then successfully defended his title against CM Punk at No Way Out and on the March 4 episode of ECW, both times pinning Punk after a frog splash.
At WrestleMania XXIV, Guerrero lost the ECW Championship to Kane in a record eight seconds. Shortly afterward, Bam Neely debuted to act as his bodyguard. Shortly after losing the ECW Championship, Guerrero had several attempts to regain the ECW Championship including losing to Kane at Backlash and also failing to become the number one contender at One Night Stand. Guerrero became involved in the Edge-Undertaker rivalry at this point, but Edge later turned on all La Familia teammates, including Guerrero. After this, Guerrero returned to singles and tag team action with Neely, feuding with ECW newcomers Evan Bourne and Ricky Ortiz, and also attempted to regain the ECW Championship at Unforgiven in a Championship Scramble match, but failed. He also was embroiled in the Undertaker-Big Show storyline, and lost a Casket match to the Undertaker on October 31. After that he tried to win the ECW Championship from Matt Hardy, but he failed to win the title.
Guerrero was drafted to the Raw brand as part of the 2009 Supplemental Draft. He then became involved in the feud between Vickie Guerrero and Santino Marella, in which he attempted to help his Aunt in law on numerous occasions. At Extreme Rules, Guerrero and his aunt faced Santina in a Hog Pen match, in which the duo lost. Upon Vickie's departure from WWE, Chavo continued to feud with Marella and defeated him on the June 18 episode of WWE Superstars.
Guerrero next feuded with Hornswoggle, where the two constantly faced off in various types of matches (in which a handicap of some sort was imposed on Guerrero by the various celebrity guests left in charge of Raw every week) with Hornswoggle gaining the win. Chavo then turned his attention towards the guest hosts themselves. On December 7, Chavo and Jillian Hall teamed up to take on Eve Torres and Hornswoggle where Eve pinned Jillian. After the match he tried to beat up Hornswoggle but Eve stood up to him. Chris Masters then came in and applied the Master Lock on him then threw him on the ground; Masters then left the ring with Eve with Hornswoggle standing over Chavo. On December 4, Chavo got an upset victory over Primo. On the January 14, 2010 episode of WWE Superstars, Chavo and Jillian faced Gail Kim and Primo where Gail Kim kicked Chavo then Primo rolled him up for the pin. Chavo then started a minor feud with Primo when Chavo and Carlito lost to Evan Bourne and Primo on the February 18 episode of WWE Superstars.
As part of the 2010 WWE Supplemental Draft, Guererro was drafted back to the SmackDown brand. On Chavo's first night back to Smackdown, Kane came out and chokeslammed him during a promo to welcome him back to Smackdown. He then started an alliance with Dolph Ziggler to feud with Christian. Guerrero and Ziggler teamed up in a tag team match against Christian and Hornswoggle, but they were defeated. The duo competed in a handicap match against Christian, which concluded in a victory at the hands of Ziggler and Guerrero. They both competed in a Battle Royal to determine who would replace The Undertaker in the World Heavyweight Championship match at Fatal Four Way, which was won by Rey Mysterio. On the July 9th episode of Smackdown, Guerrero competed in a triple threat Money in the Bank qualifying match, along with Dolph Ziggler and MVP. Throughout the match, it became apparent that Vickie Guerrero (Ziggler's manager) had told Guerrero and Ziggler to work together to ensure Ziggler qualified for Smackdown's Money in the Bank ladder match. During the match, however, when both MVP and Ziggler were down, Guerrero attempted to pin MVP to win the match himself, turning his back on Vickie and Ziggler, thus ending the alliance. Ziggler did win the match, however, by forcing MVP to submit to the sleeper hold. On the August 26th episode of WWE Superstars, Guerrero debuted a new shorter ring attire in his match with Kofi Kingston. Guerrero soon started portraying Jack Swagger's Soaring Eagle mascot, however this was later dropped.
On January 30, 2011, Chavo competed in the 2011 Royal Rumble match as the tenth entry. Chavo had a notable spot in the Royal Rumble match, attempting Three Amigos on Ted DiBiase Jr., but CM Punk disrupted him at 2 so Chavo gave them to Punk, but John Morrison breaks it up at 2, so Chavo did it to Morrison and Daniel Bryan nails him at 2 again so Chavo finally gets all Three Amigos on Bryan. Chavo was then quickly eliminated by the eleventh entrant, Mark Henry.
On March 8, Chavo was announced as a NXT Pro to Darren Young for the fifth season of WWE NXT. On the May 6 episode of SmackDown, Chavo commentated on a match between Tyson Kidd and Sin Cara, which Sin Cara won. After the match, Chavo and Sin Cara shook hands, with Chavo hinting at a future match between them. On the May 13 episode of SmackDown, Chavo interfered in the match between Sin Cara and Daniel Bryan, helping Sin Cara win. At Over The Limit, Sin Cara defeated Guerrero, and again on SmackDown (which turns out to be his last appearance on Smackdown), to end their feud. Afterwards, he mainly appeared on NXT with his rookie Darren Young. His last match in WWE was teaming up with JTG and Darren Young against Yoshi Tatsu, Conor O'Brian and Vladimir Kozlov on NXT in a losing effort.
On June 25, 2011, at his request, Guerrero was released by WWE.