Manuel Medina began his professional boxing career on September 9, 1985, beating Daniel Flores by a four-round decision in Mexicali, Mexico.
In his next fight on 5 July, he outpointed former world featherweight champion and Barry McGuigan conqueror, Steve Cruz over ten rounds.
Medina then returned to featherweight, where he won two more fights before facing Johnson in a rubber match, held on January 28, 1995 at Atlantic City.
In his next fight, Medina won the WBC's regional Fecarbox title by defeating Juan Polo Perez by a twelve-round unanimous decision on March 15 in Miami, Florida.
On April 24, 1998, Medina joined Carlos De León, Muhammad Ali, Sugar Ray Robinson, Edwin Rosario, Evander Holyfield and a small number of other boxers in the exclusive group of fighters to reign as world champions three or more times in the same division, when he outpointed defending IBF title holder Hector Lizarraga over twelve rounds in San Jose, California.
He retained the title on April 16, 1999, in Las Vegas with a nine rounds technical decision over former world super featherweight champion Victor Polo, then proceeded to lose the championship to Paul Ingle.
Medina then met future world champion Frank Toledo, beating him in Las Vegas by a ten-round decision on May 19, 2000.
Medina, meanwhile, picked up two more wins, including a fourth-round knockout over future world title challenger Mike Juarez.
Faced against former two division world champion Johnny Tapia on April 27, 2002, Medina lost the title by a twelve-round majority decision at the Madison Square Garden in New York City.
Medina's first attempt at tying Robinson's record as the only boxer to win a world title in the same division five times came on February 1, 2003, when he and Juan Manuel Márquez faced off in Las Vegas for the IBF championship vacated by Tapia.
Medina only fought once in 2004, defeating Leonardo Resendiz on July 23 at Rancho Mirage, California by a third-round knockout, to win the WBA's regional NABA super featherweight title.