He specialized in cynical, wise-cracking (and often tipsy) characters, and his rapid-fire delivery enlivened many comedies and crime thrillers in the 1930s and 1940s.

Arguably his best-known film role was the annoying bus passenger Oscar Shapeley, who tries to pick up Claudette Colbert in the Oscar-winning comedy It Happened One Night, (1934)[2] quickly followed by one of his best performances as the boozy press agent Owen O'Malley in Howard Hawks' Twentieth Century.

In 1937, Paramount teamed him with Lynne Overman as a pair of laconic private eyes in two B comedy-mysteries, Murder Goes to College and Partners in Crime.

[1] From 1950 to 1954, Karns played the title role in the popular DuMont Television Network series Rocky King, Inside Detective.

[3] From 1959 to 1962, Karns was cast as Captain (then Admiral) Walter Shafer in seventy-three of the ninety-five episodes of the CBS military sitcom/drama series, Hennesey, starring Jackie Cooper in the title role of a United States Navy physician, and Abby Dalton as nurse Martha Hale.