He initially planned to have a career as a newspaper reporter, but participation in a little theater production changed his mind, turning him toward acting.

When he returned to Hollywood, Karns portrayed his signature role as Harry Bailey in Frank Capra's Christmas classic It's a Wonderful Life (1946).

[3] He also appeared with his father Roscoe in the criminal series Rocky King, Detective (1950–1954), playing Sergeant Hart.

Karns and his wife Katherine with their three children moved to Mexico near Guadalajara where they opened the English-language venue, Lakeside Little Theater in 1971.

A newspaper reporter wrote, "His style is strictly his own and bears no resemblance to anything ever heard in an art class or put in a book.