Margaret Mayo was a stage actress from 1896 to 1903, when she retired from performing to devote herself to playwriting. Her earliest successes were adaptations of novels: The Marriage of William Ashe (1905) and The Jungle (1907). However, Mayo is best remembered as the author of more original plays such as Polly of the Circus (1907), Baby Mine (1910), Twin Beds (1914), and Seeing Things (1920), written with Aubrey Kennedy. She adapted several of her plays for the silent screen. Her play Polly of the Circus became the first film produced by the Goldwyn Company in 1917, of which she was a founding member along with her former husband Edgar Selwyn. The play was again made into a film in 1932.
Margaret Mayo was instrumental in making housing arrangements for the Indian spiritual teacher Meher Baba at Harmon, near New York City, during his fist visit to America in 1931. She owned and provided the stone house retreat where he stayed on this first trip.