The son of an Oklahoma dentist, Van Heflin moved to California after his parents separated. Drawn to a life on the sea, Heflin shipped out on a tramp steamer upon graduating from high school, returning after a year to attend the University of Oklahoma in pursuit of a law degree. Two years into his studies, Heflin was back on the ocean.
Having entertained thoughts of a theatrical career since childhood, Heflin made his Broadway bow in Channing Pollock's Mister Moneypenny; when the play folded after 61 performances, Heflin once more retreated to the sea, sailing up and down the Pacific for nearly three years.
He revitalized his acting career in 1931, appearing in one short-lived production after another until landing a long-running assignment in S. N. Behrmann's 1936 Broadway offering End of Summer. This led to his film bow in Katharine Hepburn's A Woman Rebels (1936), as well as a brief contract with RKO Radio.
Katharine Hepburn requested Heflin's services once more for her Broadway play The Philadelphia Story, and while the 1940 MGM film version of that play cast James Stewart in Heflin's role, the studio thought enough of Heflin to sign him to a contract. One of his MGM roles, that of the alcoholic, Shakespeare-spouting best friend of Robert Taylor in Johnny Eager (1942), won Heflin a "Best Supporting Actor" Oscar.
After serving in various Army film units in World War II, Heflin resumed his film career, and also for a short while was heard on radio as Raymond Chandler's philosophical private eye Philip Marlowe. He worked in both Hollywood and Europe throughout the 1950s.
In 1963, he was engaged to narrate the prestigious TV anthology The Great Adventure. He was forced to pull out of this assignment when cast as the Louis Nizer character in the Broadway play A Case of Libel. Heflin's final film appearance was in the made-for-TV speculative drama The Last Child; he died of a heart attack at the age of 61.