Matheson appeared with Kurt Russell in the 15-episode NBC series The Quest, the story of two young men in the American West seeking the whereabouts of their sister, a captive of the Cheyenne. In 1978, he co-starred in National Lampoon's Animal House opposite John Belushi; the following year, he appeared opposite Belushi again in Steven Spielberg's 1941. Matheson starred in the 1984 comedy movie Up the Creek and the comedy Fletch.
Matheson also appeared in the 1983 To Be or Not to Be starring Mel Brooks and Anne Bancroft.
Matheson and Catherine Hicks played Rick and Amanda Tucker, who operate a detective agency in Laurel Canyon in CBS' Tucker's Witch, which aired during the 1982-1983 season.