After more than a year of inactivity, Cotto returned in 2017 to become the WBO light middleweight champion, but lost the title in his final fight to Sadam Ali.

In his final amateur tournament, Cotto represented Puerto Rico as a Light Welterweight at 2000 Sydney Olympic Games where he lost to Mahamadkadir Abdullayev of Uzbekistan by points.

[11] On September 11, 2004, Cotto faced Brazilian Kelson Pinto, for the vacant World Boxing Organization junior welterweight title.

[12] Over the course of the fight Cotto scored three knockdowns and won the World Boxing Organization Junior Welterweight Championship by knockout in the sixth round.

[12] On December 11, 2004, he successfully defended his title, beating former world champion Randall Bailey by knockout in the sixth round, as part of the Vitali Klitschko-Danny Williams undercard in Las Vegas.

[14] Cotto's second title defense took place on February 26, 2005, in the Rubén Rodríguez in Bayamón, Puerto Rico, against Demarcus Corley.

"[15] Just a few days after retaining the crown versus Corley, Cotto received a personal blow, when his stablemate and friend, former 2004 Olympian Joseph Serrano, was shot in the head upon leaving the Bairoa gym.

[16] Cotto's third championship defense took place on September 24, 2005, at Boardwalk Hall in Atlantic City, New Jersey, against Ricardo Torres of Colombia.

[17] On March 4, 2006, Cotto defended his WBO Junior Welterweight title by knocking out Gianluca Branco, who had to give up during the eighth round of their bout due to a shoulder injury.

[19] Cotto relinquished his title in late 2006 and announced his intention to move to the welterweight division to challenge Carlos Quintana for the WBA's championship.

Following a punch to the body, Quintana surrendered prior to the start of the sixth round and Cotto won the vacant World Boxing Association Welterweight Championship.

[20] Cotto's Welterweight reign began successfully on March 3, 2007, when he retained his belt with a technical knock out victory in the eleventh round over Oktay Urkal.

[21] On June 9, 2007, Cotto defended the WBA Welterweight Title against Zab Judah in New York City, performing before a sellout crowd at Madison Square Garden.

[24] Cotto's performance was described as "a rare moment in sports when a sudden star rises from what is categorically termed as goodness, to the cusp of greatness.

[25] Cotto was selected the World Boxing Association's "Boxer of the Year", during the organization's annual award celebration, which took place in Buenos Aires.

[26] On July 26, 2008, at the MGM Grand in Las Vegas, Cotto suffered his first loss as a professional to Antonio Margarito in an unsuccessful title defense.

Cotto returned to action on February 21, 2009, in a card held at the Madison Square Garden, sporting the first of his trademark tattoos which he has expanded on ever since.

On June 5, 2010, he fought against undefeated Israeli WBA light Middleweight Champion Yuri Foreman at Yankee Stadium in New York City.

[41] On January 19, 2011, in a press conference at Times Square, New York, Bob Arum and Don King, working together for the first time in five years, officially announced that Cotto would defend his WBA light middleweight title against former two-division world champion Ricardo Mayorga at the MGM Grand Garden Arena in Las Vegas, Nevada, on March 12, 2011, live on Showtime PPV.

This was the same eye that was badly damaged in his fight with Pacquiao and the one that almost kept the New York State Athletic Commission from granting him his boxing license because of the special procedure that was performed on it in 2010.

[50][51] On February 1, 2012, undefeated seven-time world champion Floyd Mayweather Jr. (41–0, 25 KO's) announced that he would challenge Cotto for his WBA 'Super' light middleweight title at the MGM Grand on May 5, 2012.

[55][56] On August 31, 2012, terms were agreed for Austin Trout to defend his WBA light middleweight title against Cotto on December 1 at Madison Square Garden in New York City.

[60] On July 6, 2013, it was announced that Cotto would next fight light middleweight contender Delvin Rodríguez (28–6–3, 16 KOs) in a bout promoted by Top Rank.

[72] Throughout the fight, journalists and fans alike, noticed Martinez was unable to bend, flex and support his own weight while moving in the ring.

The scorecards at the end of the night were highly controversial as they did not show the competitiveness of the fight, with many boxing pundits having Álvarez winning by a round or two, others called it a draw.

[86][87] Cotto did not attend the post-fight press conference, but Freddie Roach in his place stated that he believed his fighter won, by outscoring Álvarez and blocking many of his shots.

[100] On May 24, it was announced a deal was made for a fight between Cotto and Kamegai to take place on August 26, 2017, at the StubHub Center in Carson, California, live on HBO.

[103][104] In front of 7,689 st the StubHub, Cotto defeated Kamegai via unanimous decision after 12 rounds to claim the vacant WBO light middleweight title and became a 6-time world champion.

[107] In September 2017, former IBF middleweight champion David Lemieux made himself available as Cotto's final opponent, which would take place on December 2, 2017, on HBO at Madison Square Garden.

[112] On October 7, ESPN reported that terms were agreed for Cotto's final fight against former Olympian and world welterweight title challenger Sadam Ali (25–1, 14 KOs) to take place on December 2 at Madison Square Garden.