Williams was a key figure in the development of African-American entertainment. In an age when racial inequality and stereotyping were commonplace, he became the first black American to take a lead role on the Broadway stage, and did much to push back racial barriers during his long career. Fellow vaudevillian W.C Fields, who appeared in productions with Williams, described him as "the funniest man I ever saw – and the saddest man I ever knew."

He and Walker performed song-and-dance numbers, comic dialogues and humorous songs. They fell into stereotypical roles: Williams the conniver, and Walker the dumb victim of his pranks.
However, they soon discovered that they got a better reaction by switching roles. Despite his thickset physique, Williams was a master of body language and physical "stage business."

In late 1896, the pair were added to The Gold Bug, a struggling musical. The show did not survive, but Williams & Walker got good reviews, and were able to secure higher profile bookings.

Williams & Walker appeared in a succession of shows, including A Senegambian Carnival, A Lucky Coon, and The Policy Players. Their stars were on the ascent, but they still faced limits placed on them by white society.

In September 1900, Williams & Walker had their greatest success to date with Sons of Ham, notable at that time for its lack of the extreme "darkie" stereotypes which were then common. One of the show's songs, "Miss Hannah from Savannah," even touched upon class divisions within the black community. The pair had already begun to transition away from racial minstrel conventions to a more human style of comedy.

From then on, the duo starred and produced a series of jits which mad them almost internationally famous.

In 1908, while starring in the successful Broadway production Bandanna Land, Williams & Walker were asked to appear at a charity benefit by George Cohan. Walter Kelly, a prominent monologist, protested and encouraged the other acts to withdraw from the show rather than appear alongside black performers. But only two of the acts joined Kelly's boycott.
Bandanna Land continued the duo's series of hits, and introduced a tour de force sketch that Williams made famous: his pantomime poker game. In total silence, Williams acted out a hand of poker, with only his facial expressions and body language conveying the dealer's up-and-down emotions as he considered his hand, reacted to the unseen actions of his invisible opponents, and weighed the pros and cons of raising or calling the bet.

Walker was in ill health by this point due to syphilis, which was then incurable. In January 1909 he suffered a stroke onstage while singing, and was forced to drop out of Bandanna Land the following month. The famous pair never performed in public again, and Walker died less than two years later. Walker had been the businessman and public spokesman for the duo. His absence left Williams professionally adrift.
After 16 years as half of a duo, Williams needed to reestablish himself as a solo act. In May 1909 he returned to Hammerstein's Victoria Theater and the high-class vaudeville circuit. His new act consisted of several songs, comic monologues in dialect, and a concluding dance.
He then starred as Mr.Lode of Kole.