O'Keefe started in films as an extra in the early 1930s, and appeared in numerous films under the name Bud Flanagan. After a small but impressive role in Saratoga (1937), Clark Gable recommended O'Keefe to MGM; he signed with them in 1937 and was renamed Dennis O'Keefe. His film roles were bigger after that, starting with Bad Man of Brimstone (1938), and the lead role in Burn 'Em Up O'Connor (1939).
O'Keefe left MGM around 1940, but continued to work in mostly lower budget productions. He often played the tough guy in action and crime dramas like Lady Scarface (1941), The Fighting Seabees (1944), The Story of Dr. Wassell (1944), T-men (1947), and Raw Deal (1948). He gave excellent performances in comedies such as Topper Returns (1940), Weekend for Three (1941), Abroad with Two Yanks (1944), Brewster's Millions (1945), Getting Gertie's Garter (1945), and The Lady Wants Mink (1953). He was the dramatic lead in films like Doll Face (1946), Dishonored Lady (1947), Woman on the Run (1950), The Company She Keeps (1950), One Big Affair (1952), and Drums of Tahiti (1954).
In the 1950s he did some directing, wrote mystery stories, and had a TV show, "The Dennis O'Keefe Show". His last two films were All Hands on Deck (1961), and Naked Flame (1964). He died of lung cancer at the age of 60.
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