In 1953, Gibson graduated from Florida Agricultural and Mechanical University. During the 1950s, she began to challenge racial segregation in tennis by playing at tournaments sponsored by the United States Lawn Tennis Association (later renamed United States Tennis Association), which had previously been restricted to white players. In 1950, Gibson became the first black competitor at the National Championships (later renamed the U.S. Open) in Forest Hills, New York. She was invited to compete only after Alice Marble, a four-time singles winner at Forest Hills, expressed her disgust at the efforts to stop Gibson from playing because of her race. In 1951, Gibson was the first black person to play tennis at the Lawn Tennis Championships at the All-England Club in Wimbledon, England.

Gibson's game slowed down in the early 1950s, at which point she worked as a physical education teacher in Missouri for two years. However, her game was revitalized by a tennis tour of Southeast Asia organized by the U.S. State Department in 1955. In 1956, Gibson won the women's singles championship at the French Open Tournament and then went on to win both the women's singles and doubles championships at Wimbledon and the U.S. National Championships at Forest Hills in 1957. In the same year, the Associated Press honored Gibson with the Female Athlete of the Year award. In 1958, she repeated her victories in the women's singles at both Wimbledon and Forest Hills.

Gibson retired from competitive tennis in 1959, turning her attention to other interests. During the 1960s, Gibson played professional golf, joining the U.S. Ladies Professional Golf Association in 1963, although she did not have the same success with golf that she had had with tennis. Gibson worked for the New Jersey state sports commission during the 1980s, and lectured and taught clinics on tennis. In 1971, she was elected to the International Tennis Hall of Fame.

During the 1990s, Gibson attempted a golf comeback and continued to speak about tennis and physical fitness in general. She authored two books: I Always Wanted to Be Somebody (1958) and So Much to Live For (1968).