Born in New York, New York, O'Brien made his film debut in 1938, and gradually built a career as a highly regarded supporting actor. During World War II, he served in the U.S. Army Air Forces and appeared in the Air Forces' Broadway play and film Winged Victory.
His other notable films include White Heat (1949), The Girl Can't Help It (1956), The Man Who Shot Liberty Valance (1962), Birdman of Alcatraz (1962), The Longest Day (1962), Fantastic Voyage (1966), and The Wild Bunch (1969). From 1950 to 1952 O'Brien starred in the radio classic " Yours Truly, Johnny Dollar", the man with the action packed expense account. He also appeared extensively in television, including the 1957 live 90-minute broadcast on Playhouse 90 of The Comedian, a drama written by Rod Serling and directed by John Frankenheimer in which Mickey Rooney portrays a television comedian while O'Brien plays a writer driven to the brink of insanity by the mayhem.
He was married and divorced from actresses Nancy Kelly and Olga San Juan. San Juan was the mother of his three children, including television producer Bridget O'Brien and actors Maria O'Brien and Brendan O'Brien.
For his contribution to the motion picture industry, Edmond O'Brien has a star on the Hollywood Walk of Fame at 1725 Vine Street, and a second star at 6523 Hollywood Blvd. for his contribution to the television industry.