Mathis turned professional in June 1965 with a second round knockout victory over Bob Maynard. Buster Mathis went on to win his next 22 contests as well and qualified for a shot at the World Heavyweight Title, which had become vacant after Muhammad Ali was stripped of the title for refusing to fight in the Vietnam War. The fight was to be held March 4 1968 in New York's Madison Square Garden and the fighter he had to beat for the championship was Joe Frazier.
Mathis made a promising start to the contest but couldn't keep up with the lighter Frazier and lost the fight by an 11th round knockout. Buster Mathis continued to fight over the next couple of years, mostly winning but never able to win the really important fights, like a 1971 fight against Muhammad Ali which he lost by a 12 round points decision.
His son Buster Mathis Jr became a succesful fighter as well and earned a 1995 fight with Mike Tyson. Buster Mathis senior, however was unable to see his son in action, as he had died at the age of 52 a couple of months before, September 6 1995.