The son of an insurance salesman, David Wayne attended Western Michigan University. While working as a statistician in Cleveland, Wayne became attracted to the local theatrical activity. Auditioning for a Shakespearean repertory company, he won the role of Touchstone in As You Like It, which he performed before an audience for the first time at the 1935 Cleveland Exposition. In 1938, he made his first New York stage appearance in Escape This Night. Classified 4F at the outbreak of World War II, Wayne volunteered for the ambulance corps, subsequently serving as a Red Cross driver in North Africa. His theatrical career really began to pick up steam after the war: cast as Og the Leprechaun in the 1947 musical hit Finian's Rainbow, he became the first actor ever to win a Tony Award. The following year, he created the role of Ensign Pulver in Mister Roberts, and in 1955 he was seen as Okinawan interpreter Sakini in Teahouse of the August Moon.
While all of his major stage roles went to other actors in the film versions, Wayne enjoyed a substantial movie career of his own. Though he made his screen debut in 1947's Portrait of Jennie, Wayne was given "and introducing" billing in the Tracy/Hepburn comedy Adam's Rib (1949), in which he played capricious composer Kip Lurie. After playing Joe, cartoonist Bill Mauldin's mud-caked infantryman, in Universal's Up Front (1951), Wayne spent most of his screen time at 20th Century-Fox, where, among other things, he did two co-starring stints with Marilyn Monroe (1952's We're Not Married, 1953's How to Marry a Millionaire), played theatrical impresario Sol Hurok in Tonight We Sing (1953), starred as a tragedy-plagued small-town barber in the underrated Wait Till the Sun Shines Nellie (1953) and portrayed schizophrenic Joanne Woodward's long-suffering husband in Three Faces of Eve (1957). One of Wayne's co-stars during his Fox years was Una Merkel, who once remarked "I loved David Wayne. I think he's one of the finest actors we have. He's so good they don't know what to do with him."
One place where they evidently did know what to do with Wayne was television, where he worked steadily from 1948 onward. Besides playing such prominent personages as Andrew Carnegie, Mark Twain and even "Old Scratch" (in a 1961 telecast of The Devil and Daniel Webster), he appeared in classic individual episodes of Alfred Hitchcock Presents and Twilight Zone, played "special guest villain" The Mad Hatter on Batman, and was a regular on the weekly series Norby (1955), The Good Life (1973), Ellery Queen (1975, as Inspector Queen), Dallas (1978), and House Calls (1980). In addition, Wayne appeared with New York's Lincoln Center Repertory, and was one of the hosts of the NBC weekend radio potpourri Monitor. Curtailing his activities in the late 1980s, David Wayne retired altogether in 1993, after the death of his wife of 51 years.