Born Emil Anton Bundmann in the Port Loma area of San Diego, he started out as an actor, appearing in plays off-Broadway in New York City. In 1938, he moved to Hollywood, where he joined the Selznick Company.

He became an assistant director in 1942, directing low-budget assignments for RKO and Republic Films. His early films were film noir movies such as Desperate, Railroaded!, T-Men and Raw Deal. These movies are well-regarded today, but Mann made his mark in the Western genre, particularly for a cycle of collaborations with James Stewart: Winchester '73 (1950), Bend of the River (1952), The Naked Spur (1953), The Far Country and The Man from Laramie (both 1955). Mann's other famous Western is Man of the West (1958), starring Gary Cooper.

Mann was respected for his acute visual sensitivity toward the American Western landscape, effortlessly blending natural vistas with human drama. Mann's dramas verged on classical tragedy, often showing anguished heroes attempting to resolve personal pain and confusion.

In the 1960s, Mann put aside Westerns to concentrate on making two epics for producer Samuel Bronston: El Cid (1961) and The Fall of the Roman Empire (1964), both intelligent and breathtaking examples of the epic form, once more demonstrating Mann's talents for merging drama with landscape and architecture.

He died from a heart attack in 1967 in Berlin, Germany while filming the spy thriller A Dandy in Aspic. The film was completed by its star Laurence Harvey).

For his contribution to the motion picture industry, Anthony Mann has a star on the Hollywood Walk of Fame at 6229 Hollywood Blvd.