Born in New York, New York of English and Irish stock, 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' Broadwayplay and filmWinged Victory.
He won an Academy Award for Best Supporting Actor for his role as a harried publicity agent in The Barefoot Contessa (1954) and was also nominated for his role as an alcoholic U.S. senator in Seven Days in May (1964). Prior to that, O'Brien had an acclaimed role in 1950's D.O.A. as a poisoned man who sets out to find his own murderer before he dies.