O'Brien's theatre work attracted the attention of Pandro Berman at RKO, who offered him a role as the romantic lead in The Hunchback of Notre Dame (1939).
O'Brien was divorced from actresses Nancy Kelly 1941–1942 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.
O'Brien made Obliging Young Lady with Eve Arden, and Powder Town. He was loaned to Universal to appear opposite Deanna Durbin in The Amazing Mrs. Holliday (1943), after which he joined the armed services.
During World War II, O'Brien served in the U.S. Army Air Forces and appeared in the Air Forces' Broadway play Winged Victory by Moss Hart. He appeared alongside Red Buttons, Karl Malden, Kevin McCarthy, Gary Merrill, Barry Nelson, and Martin Ritt. When the play was filmed in 1944, O'Brien reprised his stage performance, co-starring with Judy Holliday. He toured in the production for two years, appearing alongside a young Mario Lanza.
In 1948, O'Brien signed a long-term contract with Warner Bros., who cast him in the screen version of Lillian Hellman's Another Part of the Forest. This starred Fredric March, who also appeared with O'Brien in An Act of Murder (1948).
In 1949, 3,147 members of the Young Women's League of America, a national charitable organisation of spinsters, voted that O'Brien had more "male magnetism" than any other man in America today. "All women adore ruggedness," said organisation President Shirley Connolly. "Edmund O'Brien's magnetic appearance and personality most fully stir women's imaginative impulses. We're all agreed that he has more male magnetism than any of the 60,000,000 men in the United States today. (Runners up were Ezio Pinza, william O'Dwyer and Doak Walker.)
From 1950 to 1952, O'Brien starred in the radio drama Yours Truly, Johnny Dollar, playing the title role. His other work in radio included Philip Morris Playhouse on Broadway.
In 1951 he was in a well-publicized brawl with Serge Rubinstein at a cafe.
He made some notable movies including two for Ida Lupino, The Hitch-Hiker and The Bigamist. He also played Casca in Joseph L. Mankiewicz's film of Julius Caesar (1953).
In 1957 O'Brien recorded a spoken-word album of The Red Badge of Courage (Caedmon TC 1040). Billboard said, "Edmond O'Brien brings intensity in the narrative portions and successfully impersonates the varied characters in dialog."
From 1959–60 O'Brien portrayed the title role in the syndicated crime drama Johnny Midnight, about a New York City actor-turned-private detective. The producers refused to cast him unless he shed at least 50 pounds, so he went on a crash vegetarian diet and quit drinking.
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. Both were dedicated on February 8, 1960.
O'Brien recovered to direct his first feature Man Trap (1961).
He continued to receive good roles: The Man Who Shot Liberty Valance (1962) and The Birdman of Alcatraz (1962).
"I've never made any kind of personality success," he admitted in a 1963 interview. "People never say 'that's an Eddie O'Brien part.' They say, 'That's a part Eddie O'Brien can play.' "
O'Brien had a choice role in Seven Days in May (1964) which saw him receive a second Oscar nomination.
He was a cast member of The Other Side of the Wind, Orson Welles' unfinished 1970s movie.
In 1971, he was hospitalized with a "slight pulmonary condition."
His last works, both in 1974, were an episode of the television series Police Story and main role in the film 99 and 44/100% Dead.
O'Brien fell ill with Alzheimer's Disease. In a 1983 interview, his daughter Maria remembers seeing her father in a straitjacket at a Veterans' Hospital.
O'Brien followed this with a number of important roles, including Pete Kelly's Blues, 1984, A Cry in the Night (1956), and The Girl Can't Help It.
He died May 9, 1985, at St. Erne's Sanitorium in Inglewood, California, of Alzheimer's disease. He was survived by his three children.
"The funny thing about Hollywood is that they are interested in having you do one thing and do it well and do it ever after," said O'Brien. "That's the sad thing about being a leading man – while the rewards may be great in fame and finances, it becomes monotonous for an actor. I think that's why some of the people who are continually playing themselves are not happy."
