After turning professional in 1989, Bowe went on to become a two-time world heavyweight champion. In 1992 he won the undisputed WBA, WBC and IBF titles by defeating then-unbeaten former undisputed cruiserweight champion Evander Holyfield. That same year, Bowe was named Fighter of the Year by The Ring and the Boxing Writers' Association of America. Bowe vacated the WBC title later that year in protest, instead of defending the title against their number one contender, Lennox Lewis. This left the undisputed championship fragmented until 1999. In a rematch with Holyfield in 1993, Bowe narrowly lost the WBA and IBF titles in what would be his only professional defeat.

He later regained a portion of the world heavyweight championship in 1995, defeating Herbie Hide for the then-fledgling WBO title. In doing so, Bowe became the first boxer in history to win the titles of all four major sanctioning bodies—the WBA, WBC, IBF and WBO—and remains the only heavyweight to do so. Later that year, Bowe vacated the WBO title in order to fight Holyfield for a third time, and won decisively by being the first boxer to defeat Holyfield by knockout. 1996 saw Bowe engage in two brutal slugfests with Andrew Golota, both of which ended controversially when Golota repeatedly hit him with low blows.

Bowe retired from boxing after the Golota fights, making low-key comebacks in 2004 and 2008. In a 2010 article by BoxingScene, Bowe was ranked the 21st greatest heavyweight of all time. In 2015, he was inducted into the International Boxing Hall of Fame.

This Everlast boxing glove was signed in black by Bowe and includes a JSA sticker and COA.