While a struggling performer in New York City, Sanford adopted the name Redd Foxx. He performed comedy on the “chitlin circuit” of African American nightclubs during the 1940s and '50s. By the 1960s, recordings of his comedy acts had become enormously popular among African Americans, though his albums were considered too racy for white audiences and were rarely available in stores with predominantly white customers.

In 1970 he gave a memorable comic performance in the hit film Cotton Comes to Harlem, and soon afterward he was approached by television producer Norman Lear about starring in the American version of the popular British sitcom Steptoe and Son. In Sanford and Son, Foxx played Fred Sanford (the name was taken from his brother), a junk dealer and widower living with his son in the Watts neighbourhood of Los Angeles. The show was a major success, but a dispute between Foxx and the producers over the direction of the show led to his departure in 1977. The Redd Foxx Comedy Hour (1977–78) and The Redd Foxx Show (1986) followed, but both shows were short-lived.

Foxx occasionally made films, including Harlem Nights (1989) with Eddie Murphy (Murphy, Eddie), but worked primarily as a Las Vegas headliner. He was shooting a new sitcom named The Royal Family when he died in 1991.