[3][4][5] In 2009, just before his fight with Shane Mosley, Margarito was involved in an incident where he was caught with illegal hand wraps containing gypsum (calcium sulfate) which, when combined with moisture, forms plaster of Paris.

[6][2][7][8] He compiled a record of 18–3 in his relatively brief amateur career, indicating that he may have turned pro quickly due to financial concerns (which he himself confirmed on his personal television segment on HBO: Ring Life: Antonio Margarito).

Following that, his financial situation dramatically improved (which is what he was trying to achieve early on in his career) and from there he went 28–2–1, with notable wins over Alfred Ankamah, Juan Soberanes, future World Middleweight Champion Sergio Martínez, Buck Smith, David Kamau and Frankie Randall, a former World Light Welterweight Champion who became the first man to beat Julio César Chávez in 91 fights.

The fight had to be stopped in the first round as a consequence of a clash of heads that opened deep gashes on both fighters and sent them both to a nearby hospital.

[9][10] He defended that crown with a decision in twelve over Danny Perez Ramírez and a knockout in two over former WBA title holder Andrew Lewis.

At this point, Margarito considered going up in weight to try to lure Fernando Vargas, Oscar De La Hoya or Shane Mosley into a lucrative fight, or Santos into a rematch at the light middleweight division.

On October 17, 2003, Margarito made his light middleweight division debut with a two-round knockout win over Maurice Brantley in Phoenix, Arizona.

On January 31, 2004, back in the welterweight division, he retained his title with a second-round knockout of Canada's previously undefeated Hercules Kyvelos.

On April 23, 2005, Margarito retained his WBO welterweight title against another Puerto Rican, undefeated world class puncher Kermit Cintron, dropping him four times on his way to a fifth-round knockout (this fight was televised by ESPN Pay-Per-View Boxing).

On July 14, 2007, Margarito lost a 12-round unanimous decision to undefeated challenger Paul Williams, losing his WBO belt.

[15] Following his successful rematch with Cintron, the IBF ordered him to fight a mandatory defense against the organization's number-one contender, Joshua Clottey, whom Margarito had previously defeated in 2006.

[22] Margarito was scheduled to return to the ring on March 13, 2010, against Carson Jones, pending his relicensing, on the Pacquiao-Clottey undercard.

[23] Margarito expressed interest in fighting Filipino boxer Manny Pacquiao if the latter's bout with Floyd Mayweather Jr. did not materialize.

His comeback fight was postponed until May 8 and was held at Aguascalientes, Mexico, where he faced light middleweight contender Roberto García (28–2).

[24] Margarito won a ten-round unanimous decision over García to capture the vacant WBC International Light Middleweight title.

[29][30] In his camp for this fight, Margarito had four southpaw sparring partners: Karim Martínez, Cleotis Pendarvis,[31] number one mandatory for the WBA Light Middleweight title, Austin Trout, and U.S. Olympic silver medalist Ricardo Williams.

[39] This was the same eye that was badly damaged in his previous fight with Manny 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.

He faced Carson Jones on September 2, 2017, winning a slugfest by seventh-round technical decision after a cut opened up on Margarito's eye in the early rounds.

[45] In late January the California State Athletic Commission suspended Margarito and his trainer, Javier Capetillo, pending investigation.