Foxx was born in St. Louis, Missouri and raised on Chicago's south side. His mother was part Cherokee Indian. His father, an electrician, left the family when Foxx was four. He was raised by his mother, a minister, and his grandmother. He briefly attended DuSable High School with future Chicago mayor Harold Washington, but never graduated. During World War II, Foxx used illegal means to avoid the draft and engaged in various criminal activities. Moving to New York in the early 1940s, he was a well-known associate of Malcolm Little, later known as Malcolm X. According to Malcom's autobiography, Foxx was a dishwasher in the speakeasy where Malcom worked as a waiter. (While Little was known as "Detroit Red" from having grown up in Michigan, Foxx was dubbed "Chicago Red," due to his "ruddy complexion". His second stage name was taken from baseball star Jimmie Foxx).

Foxx gained notoriety with his raunchy nightclub act. His stand-up performances were later released as "party" albums and became very popular. Foxx paved the way for later black comedians such as Richard Pryor, Eddie Murphy, and Chris Rock. He was also one of the first black comics to play to white audiences on the Las Vegas Strip. Foxx used his starring role on Sanford and Son to help get jobs for his friends such as LaWanda Page, Slappy White, and Noriyuki "Pat" Morita. Foxx also battled with producers Norman Lear and Bud Yorkin for higher paychecks and creative control of the show.

In 1977, Sanford and Son was canceled and Foxx struck out on his own by starring in a short-lived variety show, but by the early 1980s he was back playing Fred Sanford in a brief revival/spin-off, Sanford. Foxx had numerous battles with the IRS that culminated in a 1989 "raid" in which agents seized his house and assets. Foxx appeared to be making a comeback with the 1991 series The Royal Family, in which he co-starred with his long-time friend Della Reese when a fatal heart attack felled him on the set. Ironically, one of Foxx's best-known comic bits on Sanford and Son was faking a heart attack and calling out to his deceased wife Elizabeth saying "this is the big one...I'm comin' to join ya, honey".