- At the age of 10 he learned conjuring tricks from his neighbor, Harry Houdini.
- In an interview, director Don Siegel recalled that during the production of China Venture (1953), he noticed that O'Brien was spending more and more time in his trailer before a scene, and was beginning to arrive late for shooting, which he had never done before. Suspecting that O'Brien might be secretly drinking before he went on camera--an experience Siegel had undergone with several well-known actors he had worked with--the director peeked through the windows of O'Brien's trailer one day and was surprised to see a young man reading O'Brien's lines to him. It turned out that O'Brien's eyesight and memory were beginning to fail him, he didn't want the studio to find out and fire him, so he had his assistant read him his lines and stage directions immediately before he was to shoot a scene so he wouldn't forget them on-camera.
- Was cast in Black Christmas (1974) as Lt. Kenneth Fuller, but the part was re-cast with John Saxon because of O'Brien's poor health. He was rumored to be suffering from Alzheimers.
- Served with the US Army Air Force in World War II.
- O'Brien was originally cast as the photo-journalist Jackson Bentley (based on Lowell Thomas) in Lawrence of Arabia (1962). After O'Brien filmed several scenes, he suffered a heart attack and had to drop out of the picture. He was replaced by Arthur Kennedy.
- In his film debut, The Hunchback of Notre Dame (1939), O'Brien was slender and had the looks of a romantic leading man. But he quickly put on weight and developed jowls that made him appear older than he actually was. After World War II he was typed as a character player.
- He appeared in two films that depicted the Normandy landings on 6/6/44: D-Day the Sixth of June (1956) and The Longest Day (1962). D-Day veteran Richard Todd also appeared in both films.
- His production company, Tiger Productions, came from his childhood nickname, 'Tiger'.
- Often played characters with drinking problems and may have been an alcoholic in real life.
- As of 2023, the only actor to win an Oscar for playing a character named Oscar.
- Appeared in three Oscar Best Picture nominees: The Greatest Show on Earth (1952), Julius Caesar (1953) and The Longest Day (1962). Only the first of these won.
- Interred at Holy Cross Cemetery, Culver City, CA. Specific Interment Location: F, T54, 50.
- He has appeared in six films that have been selected for the National Film Registry by the Library of Congress as being "culturally, historically or aesthetically" significant: The Killers (1946), White Heat (1949), D.O.A. (1949), The Hitch-Hiker (1953), The Man Who Shot Liberty Valance (1962) and The Wild Bunch (1969).
- Father, with Olga San Juan, of actress Maria O'Brien, TV producer Bridget O'Brien Adelman and Brendan O'Brien.
- Younger brother of Liam O'Brien.
- Ex-father-in-law of Michael Anderson Jr..
- Father-in-law of Ingrid K. Behrens (wife of son Brendan O'Brien).
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