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 lieutenant Happened One Night (1934). From 1950 to 1954, Karns played the title role in the popular DuMont Television Network series Rocky King, Inside Detective.
From 1959 to 1962, Karns was cast as Admiral Walter Shafer in seventy-three of the ninety-five episodes of the Columbia Broadcasting System 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.
Karns was born in San Bernardino, California, and died in Los Los Angeles