After a brief retirement after losing twice to Junior Jones, Barrera revived his career with a trilogy against Erik Morales and a win against Naseem Hamed, earning him the Ring magazine featherweight title.
In 1990, Barrera had seven fights, including his first rise in quality opposition, when he defeated veteran Iván Salazar, by a decision in eight rounds.
On March 31, he became the WBO super bantamweight champion by defeating Puerto Rican boxer Daniel Cobrita Jiménez by a decision in twelve rounds at Anaheim, California.
In one of the fights of the year, Barrera stopped Kennedy McKinney in 12 rounds, knocking him down five times whilst suffering one knockdown himself.
On November 22, 1996, he suffered his first career loss and lost his title to American boxer Junior Jones, by a disqualification in round five.
On October 31, he became a two-time world super bantamweight champion by defeating Richie Wenton by a knockout in three rounds, winning the WBO's vacant title.
But upon finding out that Najera had a losing record and was part of Barrera's team, the California State Athletic Commission decided to rule the fight a no contest bout.
In February 2000, Barrera was defeated by the WBC super bantamweight title holder Erik Morales by a controversial 12 round split decision.
On April 7, he handed British boxer Naseem Hamed his first and only loss for the lineal featherweight championship by a twelve-round decision.
In the 12th and final round Barrera trapped Hamed in a full nelson and forced his head into the turnbuckle, resulting in a point deducted by referee Joe Cortez.
Barrera was awarded the victory via a unanimous decision, with the scorecards reading 115–112, 115–112, 116–111 and won the lineal and IBO featherweight titles.
[11] Barrera then competed in his 60th career fight on 12 April 2003, defeating former WBC title holder Kevin Kelley by knockout in round four.
On June 19, 2004, Barrera defeated former WBA bantamweight title holder Paulie Ayala in Los Angeles by a tenth-round knockout.
[15] On May 20, 2006, Barrera defended his title against American boxer Rocky Juárez with what was announced immediately after the fight as a twelve-round draw, which the judges scored 115–113, 113–115 and 114–114.
However, tabulation errors were found in the judges' scorecards, leading to a final score of 115–114, 114–115 and 115–114, a split decision in favor of Barerra.
[16] On March 17, 2007, Barrera lost his WBC super featherweight title to fellow Mexican boxer Juan Manuel Márquez by unanimous decision.
Even without counting a knockdown of Marquez that was ruled a slip by referee Jay Nady in the 7th round, Harold Lederman of HBO had the fight in favor of Barrera.
[17] Barrera fought Pacquiao in a rematch bout for the WBC International super featherweight title on October 6, 2007, in Las Vegas.
Marco Antonio Barrera, at 35, ended his brief retirement and signed a five-year contract on August 26, 2008, with promoter Don King.
[20] On November 7, 2008, Barrera marked his return to the ring, in Chengdu, China, by knocking out Sammy Ventura in his first bout in the lightweight division.
On February 12, 2011, he fought Jose Arias of the Dominican Republic and scored a TKO in the second round; this was to be Barrera's final fight.