Tim Witherspoon turned professional in 1979 after just five amateur bouts. He worked as a sparring partner for Muhammad Ali when the former champion was training for his ill-fated comeback fight against Larry Holmes in 1980. Witherspoon also briefly worked as a sparring partner for Gerry Cooney. "I lasted three days," Witherspoon said. "When I bloodied his nose, they told me to take a walk."
In May 1983, with a record of 15-0, Witherspoon fought Larry Holmes for the World Heavyweight Championship and lost by a twelve-round split decision.
Witherspoon defeated Tony Tubbs by a fifteen-round majority decision in January 1986 to win the WBA Heavyweight Title and successfully defended it with an eleventh-round TKO of Frank Bruno in July 1986.