On January 14, 1994, he beat Jose Trujillo in Tijuana by decision in four rounds, to make his professional debut.On April 25, he achieved his first knockout win, defeating Victor Angulo in the second round. On October 17, however, he suffered his first defeat, to Victor Lozoya, by decision in six. Over the course of his next six bouts, he lost two. However, he went onto a winning streak after that loss that has so far, reached twenty wins in a row, not including his fight with Daniel Santos, which ended in a no contest. Before getting to fight with Santos, he beat such fighters as Alfred Ankamah, Juan Soberanes and former Julio Cesar Chavez rivals Buck Smith, David Kamau and Frankie Randall, a former World Jr. welterweight champion who became the first man to beat Chavez in 91 fights.
On July 21, 2001, he received his first world title try, against Santos, for the WBO world Welterweight crown, at Bayamon, Puerto Rico's Ruben Rodriguez Coliseum. 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. Because the fight had not gone over the reglamentary four rounds or more for a technical decision to be awarded, it was declared a no contest, and Santos retained the belt but without adding a loss to Margarito's record.
Santos then vacated the WBO world Welterweight title to pursue the WBO's world Jr. Middleweight championship, and Margarito was assigned to fight Antonio Diaz for the vacant world crown, in front of an HBO Boxing audience. On March 16, 2002, Margarito crowned himself world champion by beating Diaz by knockout in round ten. He defended that crown with a decision in twelve over Danny Perez and a knockout in two over former world champion Andrew Lewis.
Margarito has decided to go up in weight, to try to lure Fernando Vargas, Oscar De La Hoya or Shane Mosley into a fight, or Santos into a rematch at the Jr. Middleweight division. He is still also actively looking for an unification bout with WBC and WBA world champion Ricardo Mayorga. On October 17, 2003, Margarito made his Jr. Middleweight division debut with a two round knockout win over Maurice Brantley in Phoenix, Arizona.
Margarito has a record of 29 wins, 3 losses and 1 no contest, with 20 wins by knockout.