McDonald's started acting professionally in stock theater with the Forepaugh Stock Company in Cincinnati. Following eight months with it, he worked one season with a stock company in Seattle, after which he performed for three seasons with a troupe in San Diego and Honolulu. He concluded his tenure in stock theater as juvenile leading man with the American Stock Company in Spokane, Washington.

By 1913 McDonald began to perform in the rapidly expanding film industry, initially working for Marion Leonard's Monopole Company in Hollywood. He was cast in over 280 films between 1913 and 1965, including The Temptress in 1926 with Greta Garbo. After he was designated "Hollywood's Prettiest Man," McDonald sought a tougher image by shaving his mustache and seeking roles of villains.

McDonald was one of Cecil B. DeMille's favorite character actors.[citation needed] DeMille gave him credited supporting roles in six of his films: The Plainsman (1936), The Buccaneer (1938), Union Pacific (1939), North West Mounted Police (1940), Samson and Delilah (1949), and The Ten Commandments (1956).