Ruby Keeler moved as a young child with her family to New York City and grew up poor on the Lower East Side. She started taking dance lessons at 10 years old and learned to tap dance. At 13 she began her show business career in the chorus line of the George M. Cohan Broadway production of The Rise of Rosie O'Reilly in 1923. When legendary producer Flo Ziegfeld spotted her in a musical called Lucky, he signed her up to star in Whoopee alongside Eddie Cantor.

Before Whoopee made it to the Broadway stage Ruby Keeler travelled to Hollywood for a small part in a short, Show Girl in Hollywood. There she married singer Al Jolson (star of the first "talkie," The Jazz Singer) in 1928. She returned to New York with Jolson, but was soon back in Hollywood for a brief, memorable career in film. In her 1933 debut, 42nd Street, Keeler played a chorus girl suddenly sent onstage to replace the ailing lead dancer, the director urging her on with the immortal lines, "You're going out there a youngster, but you've got to come back a star!"

The feature 42nd Street was followed by Warner Bros. tap-dancing musicals that became classics of the genre thanks to the spectacular, geometrically patterned routines choreographed by Busby Berkeley: Gold Diggers of 1933 and Footlight Parade in 1933, and Dames in 1934. Ruby Keeler made her last film in 1941, divorced Jolson, and retired from the screen to raise a family with her second husband.

With the revival of interest in Busby Berkeley's films in the late 1960s, Ruby Keeler made a brief comeback at age 61 to perform her tap-dancing numbers to critical acclaim in the 1971 Broadway revival of No, No, Nanette.