Coburn became famous as the "tough guy" in a variety of films, first mostly with his friends Robert Vaughn and Charles Bronson (whom he co-starred with in The Magnificent Seven and The Great Escape). In 1966, Coburn finally became a bona-fide star with the release of Our Man Flint, a James Bond spoof released by 20th Century Fox as competition. After a sequel, Coburn decided to branch off into the independent film world. Due to his interests in karate (which he discovered by training with Bruce Lee), Buddhism, and gong-playing, the remainder of the decade (which included less-than-forgettable films), proved uneventful to Coburn.

In 1973, however, Coburn teamed up with radical director Sam Peckinpah for the film Pat Garrett & Billy the Kid (they had first worked together in 1965 on Major Dundee). But Peckinpah's drinking and budget problems caused the film to be drastically edited when it opened. Both Peckinpah and Coburn were disappointed and delved into Cross of Iron, a war epic which also flopped. The two still remained good friends until the legendary director's death in 1984 of a stroke.

Due to severe rheumatoid arthritis, he appeared in very few films during the 1980s. He claimed to have healed himself with pills containing sulfur, and returned to screen in the 1990s.

He then appeared in films such as Young Guns II (1990), Sister Act 2 (1993), The Nutty Professor (1996), and Maverick (1994) mostly in small but memorable roles. For his appearance as the abusive father of protagonist Nick Nolte in Affliction he received an Academy Award for Best Supporting Actor in 1998.

He died suddenly on November 18, 2002 from a heart attack, at the age of 74.