Le Mat starred in the pilot episode of Firehouse in 1973. In the same year, he appeared in American Graffiti, a coming-of-age film about a group of friends in Modesto, California in the early 1960s. He played John Milner - a role that would earn him his first Golden Globe Award. Le Mat also starred in Floyd Mutrux's 1975 crime spree film Aloha, Bobby and Rose, another commercial hit.
In 1977, he starred in Jonathan Demme's acclaimed comedy Citizens Band, later re-titled Handle with Care. Le Mat would reunite with Demme for 1980's Melvin and Howard, in which he played the title role of Melvin Dummar. The film was based upon the true story of a gas station attendant who claimed to be an heir of eccentric billionaire Howard Hughes, and it won two Academy Awards. Le Mat was nominated for a Golden Globe Award. In 1979, Le Mat reprised his role of John Milner in More American Graffiti.
In 1982, Le Mat played the character John Dortmunder in Jimmy the Kid, opposite Gary Coleman in the role of Jimmy. He also provided the voice of Omar in the American release of the animated film Rock & Rule. Le Mat starred in the made-for-TV movie The Burning Bed with Farrah Fawcett. The film was based on the true story of an abusive husband who drives his wife to drastic measures with his aggressive ways. Le Mat was awarded the second Golden Globe Award of his career for his role in the film. He starred in other television films such as The Night They Saved Christmas, Into the Homeland and Secret Witness. He appeared in the TV miniseries On Wings of Eagles and in the film Puppet Master.