Cassavetes majored in English at Colgate University before studying acting at the American Academy of Dramatic Arts in New York City (1950). A method actor, he made his motion-picture debut as an extra in 14 Hours (1951) and his first television appearance in an episode of “Omnibus” in 1953. Although Shadows (1960), his directorial debut, was a low-budget, semi-improvised motion picture shot on 16-millimetre film stock, it captured the Critics Award at the 1960 Venice Film Festival. This success earned him two movie studio commissions, Too Late Blues (1962) and A Child Is Waiting (1963), both of them commercial failures. Specializing in villainous roles, he appeared as an actor in a number of motion pictures, including The Dirty Dozen (1967) and Rosemary's Baby (1968).

As a director, Cassavetes was masterful in dramatizing marital problems, notably in such independent films as Faces (1968), Husbands (1970), and A Woman Under the Influence (1974), which starred his wife, Gena Rowlands. Some of his other directorial efforts include The Killing of a Chinese Bookie (1976), Love Streams (1984), and Big Trouble (1986).