O'Keefe was born in Hartford, Connecticut. He attended the College of the Sacred Heart in Wimbledon, London before entering the University of Notre Dame in South Bend, Indiana in 1916. At Notre Dame, he was a member of the Glee Club and a Class Poet. He graduated cum laude in 1921.
O'Keefe began as a vaudeville performer in the midwest for several years. In 1925, he went to New York and became a Broadway performer. By 1937, he wrote a syndicated humor column and filled-in for such radio personalities as Walter Winchell, Edgar Bergen, Don McNeill and Garry Moore. He became the long-time master of ceremonies of the NBC show Double or Nothing and was a regular on that network's Monitor series.
O'Keefe also worked in television, presiding over talk shows and quiz shows for the CBS network. Producers Mark Goodson and Bill Todman hired him for their game show Two for the Money. When the show's usual host, Herb Shriner, had other commitments during the summer of 1954, O'Keefe took over for three months. He was the host for the first Emmy Awards ceremony, held on January 25, 1949 at the Hollywood Athletic Club.
O'Keefe was also a songwriter responsible for the musical scores of several Hollywood films. He introduced the very popular song "The Daring Young Man on the Flying Trapeze" in 1934, and it became permanently associated with him.
- 1929 The Sophomore - actor and music composer
- 1929 Red Hot Rhythm - actor, music composer and lyricist
- 1930 Dancing Sweeties - music composer
- 1930 Sweet Kitty Bellairs - music composer
- 1931 The Smart Set-Up - actor
- 1935 Vagabond Lady - music composer and lyricist
- 1936 Prison Shadows - actor
- 1938 Go Chase Yourself - screenwriter
- 1941 Too Many Blondes - music arranger
- 1952 Two for the Money (TV Series) - guest host
- 1954 Screen Snapshots: Hollywood Stars on Parade - himself
- 1956 The NBC Comedy Hour (Episode #1.16) - actor (himself)