Canizales turned professional in 1984 and was undefeated in twelve fights (one fight was a draw) before meeting the 1984 Olympic gold medalist Paul Gonzales in 1986. Gonzales defeated him over twelve rounds. Canizales rebounded from that defeat, however, and on July 9, 1988, he won the IBF bantamweight title by knocking out defending titlist Kelvin Seabrooks in the fifteenth round. He tied the division record for consecutive title defences at 15 set by Manuel Ortiz. His victims included old foe Gonzales, former flyweight champion Rolando Bohol, British champion Billy Hardy, and future champion Clarence “Bones” Adams. Many people incorrectly state that Orlando Canizales made 16 consecutive defences. This is due to many of them counting a no contest with Derrick Whiteboy as a title defence. No contests are not title defences however as the champion can’t defend his title in a match that isn’t considered to be a proper boxing contest.

In January 1995, Canizales attempted to win a title in the junior featherweight division. World Boxing Association champion Wilfredo Vazquez prevented him from doing so, winning a twelve-round split decision.

He was inducted into the International Boxing Hall of Fame on July 14, 2009. With his parents watching, an emotional Canizales approached the podium and delivered a heartfelt speech. “Boxing has taught me a lot in life — that dedication, discipline and determination will pay off in the long run and not to be easily swayed by obstacles and bumps in the road.”

The Orlando & Gaby Canizales Boxing Gym and Community Center on Guadalupe Street in Laredo is named in honor of the boxing brothers. The facility was expanded in 2014.