O'Keefe started in films as an extra in the early 1930s. After a small but impressive role in Saratoga, Clark Gable recommended O'Keefe to Metro-Goldwyn-Mayer, which signed him to a contract in 1937. His film roles were bigger after that, starting with The Bad Man of Brimstone and Burn 'Em Up O'Connor.

O'Keefe left MGM around 1940 but continued to work in mostly lower budget productions. In the 1950s he did some directing, wrote mystery stories and by the mid-1950s found work on television shows such as Justice, The Martha Raye Show, The Ford Show as well as his own series The Dennis O'Keefe Show.