His first performance on WWE's main roster was in a dark match that took place before the December 15, 2003 Raw tapings.
On October 7, 2004, Carlito made his debut as a heel on SmackDown! as "Carlito Caribbean Cool" (though later shortened to simply "Carlito"), whose gimmick was an apple toting big mouth who would spit apple "in the face of people who don't want to be cool". Carlito defeated John Cena for the United States Championship in his first match on the main roster by using a steel chain to knock out Cena. Carlito was then involved in a storyline where his bodyguard Jesús stabbed Cena in a nightclub. Carlito held the United States Championship for forty-two days, losing it back to Cena after suffering a legitimate injury. Carlito made his pay-per-view debut at the 2004 Survivor Series, where he represented Team Angle in an eight man tag team match against Team Guerrero, but did not actually participate in the event after being chased out of the building by Cena.
While Carlito was recovering from an injury, he was involved in a comical angle with SmackDown!'s general manager, Theodore Long. The storyline consisted of Carlito being forced to do demeaning chores around the arena, such as selling hot dogs, removing snow from parking lots with a shovel and mopping floors. As a result of these actions, Carlito created a petition in support of Long’s destitution, but was unsuccessful. Carlito made his WrestleMania debut in a non-wrestling role at WrestleMania 21, in which he interrupted an edition of Rowdy Roddy Piper's Piper's Pit, with Stone Cold Steve Austin as the special guest. Following WrestleMania, Carlito created an interview segment entitled Carlito’s Cabana. Carlito then entered a feud with The Big Show after a spot where Show refused an offer to work in an enforcer role for Carlito. This feud involved Carlito tricking Show into eating a poisoned apple, and Matt Morgan becoming Carlito's enforcer. This feud ended with Carlito defeating Show at Judgment Day.
Carlito was drafted to the Raw brand in the 2005 WWE Draft Lottery, where he defeated Shelton Benjamin for the Intercontinental Championship in his debut match for the brand. He then lost the Intercontinental title to Ric Flair at Unforgiven. Towards the end of 2005, Carlito was involved in a brand rivalry which led to him discontinuing Carlito's Cabana. The angle concluded with Carlito wrestling for Team Raw against Team SmackDown! in a ten man tag team match at the Survivor Series.
In late 2005, Carlito was added to angles involving the WWE Championship. After defeating Shelton Benjamin in a qualifying match, Carlito was added to the main event at New Year's Revolution in early 2006, the Elimination Chamber match. He was one of the final two wrestlers remaining, after eliminating Kane, Chris Masters and Shawn Michaels. He then lost the match to John Cena.
Following New Year's Revolution, Carlito and Chris Masters joined forces as a tag team. Together they competed against Big Show and Kane for the World Tag Team Championship at WrestleMania 22. Carlito and Masters lost when Masters accidentally attacked Carlito. Following the match, Carlito confronted Masters, igniting a feud between them. Carlito then turned face when he attacked Chris Masters after his "Masterlock Challenge" the next night on Raw. This storyline came to a conclusion at Backlash, where Carlito defeated Masters via an illegal assist from the ropes.
At Vengeance, Carlito fought in a Triple Threat match against Shelton Benjamin and Johnny Nitro for Benjamin's Intercontinental title. Nitro won the match after pulling Carlito outside of the ring and pinning him. Following Vengeance, Carlito began an on-screen relationship with Trish Stratus, turning face as a result. He also engaged in a short feud with Johnny Nitro and Melina, which ended after Carlito and Stratus defeated Nitro and Melina in a mixed tag team match at Saturday Night's Main Event. Carlito next feuded with Randy Orton, following a spot where Orton attempted to attack Stratus during a backstage segment. The two wrestlers were booked for a match at Unforgiven and a rematch on Raw; Orton won both matches. The feud concluded in a match at WWE’s annual Tribute to the Troops event, where Carlito won by pinfall. The angle involving Carlito's relationship with Trish Stratus lasted until Stratus' retirement from wrestling following Unforgiven.
In the final months of 2006, Carlito competed in several matches involving the Intercontinental Championship. His involvement in this angle ended at Cyber Sunday 2006, after being elected by the fans to face Jeff Hardy for the championship. Carlito, however, lost the match. During this time period Carlito's gimmick underwent a slight change and was sold as a "ladies man", eventually getting involved in another fictional relationship with Torrie Wilson.
Carlito participated in the 2007 Royal Rumble, where he was eliminated by The Great Khali. Following the Royal Rumble, Carlito started a feud with Ric Flair, in which Flair insulted Carlito for leaving a show early by claiming that he had no heart, no passion and was undeserving of his spot on the roster. After Carlito challenged and lost to Flair in a match, they were booked as a tag team, with Flair serving as a mentor to Carlito. The team was involved in a Money in the Bank qualifying match which was declared a "no contest" after The Great Khali interfered. This led to a triple threat match the following week which included and was won by Randy Orton.
He participated in a dark match at WrestleMania, winning in a tag team match with Flair as his partner against the team of Chavo Guerrero and Gregory Helms. The team also lost a number one contender's match for the World Tag Team Championship against Lance Cade and Trevor Murdoch. Carlito turned on Flair after the loss, which turned him heel again. Their feud ended with a match at Judgment Day, where Carlito lost to Flair by submission.
Following his feud with Flair he was involved in angles with The Sandman and Triple H. He then lost to Triple H at Unforgiven 2007 in a no disqualification match where the no disqualification rule only applied to Carlito.
On December 10, 2007, he was featured in a ladder match at the Raw 15th Anniversary against Jeff Hardy for the WWE Intercontinental Championship, which Hardy won. Carlito defeated Cody Rhodes to qualify for the money in the bank ladder match at Wrestlemania 24. He failed to win at the event. Carlito then formed a tag team with Santino Marella. The team was placed in several matches involving the World Tag Team Championship, twice being named the number one contenders; however, they lost the relevant championship matches.
As part of the 2008 WWE Supplemental Draft, Carlito was drafted back to the SmackDown brand.
On September 12, he re-debuted on the brand turning face, forming a tag team with his brother, Primo. They defeated WWE Tag Team Champions Curt Hawkins and Zack Ryder in the match to gain their first victory as a team. Two weeks later, both teams competed in a title match, with The Colóns winning to become tag team champions. Subsequently, Carlito and Primo entered a feud with World Tag Team Champions John Morrison and The Miz. At WrestleMania XXV, The Colóns defeated Miz and Morrison in a tag team unification match, becoming the first team to simultaneously hold both sets of the company's Tag Team Championships since their creation.
On April 15, 2009, both Carlito and Primo were drafted back to the Raw brand as part of the 2009 Supplemental Draft. At The Bash, the duo dropped the Unified Tag Team Titles to Edge and Chris Jericho in a Triple Threat Tag Team Match also involving Ted DiBiase and Cody Rhodes. Carlito and Primo invoked their rematch clause the next night on Raw, but were unsuccessful.
On the July 6 episode of Raw, following their loss to Edge and Jericho, Carlito turned heel by attacking Primo. At Night of Champions, Carlito challenged for the United States Championship in a Six-Pack Challenge, which also involved Primo, but neither of them were able to win the title. On the August 3 episode of Raw, Carlito defeated Primo to end their feud. On the August 13 episode of WWE Superstars, Carlito teamed with Rosa Mendes to defeat Kofi Kingston and Mickie James. Mendes would then become Carlito's manager until she was traded to the ECW brand in September.
After a two-month hiatus, on the November 30 episode of Raw, Carlito returned to confront John Cena, after Cena challenged Sheamus to come out to the ring, telling him everyone on the roster were tired of him and that Sheamus was there representative of what the roster believed and then tried to spit apple in Cena's face, which led to him getting hit with Cena's finisher, the Attitude Adjustment. The following week, Carlito was defeated by Cena.
In February 2010, Carlito was announced as one of the eight WWE Pros for the first season of WWE NXT. On the February 22 episode of Raw, Carlito was defeated by Christian in a Money in the Bank Qualifying match. The next night on WWE NXT, Carlito teamed with his NXT Rookie Michael Tarver in a losing effort against Christian and his NXT Rookie Heath Slater. On the May 2 episode of WWE Superstars, during his match with Primo, Carlito would stop the match and told Primo they shouldn't fight when the crowd cheers for two brothers to fight each other. Primo would agree and reunite with his brother, turning heel in the process. On the May 10 episode of Raw, Carlito and Primo attacked R-Truth for Ted DiBiase, who paid them afterwards. On May 21, Carlito was released.
On April 3, 2014, Carlito, along with his brother Primo (then known as Diego), and their cousin Epico (then known as Fernando), inducted his father Carlos Colon into the WWE Hall of Fame.