Allison was born in Rising Fawn, Georgia, the youngest of five children born to Dr. John Simon (Sam) Allison and Nannie Virginia (Wise) Allison.  Violet eyed, Allison made her Broadway stage debut in the 1914 production of Apartment 12-K before settling in Hollywood, California in the early days of motion pictures. Allison’s screen debut was as an ingenue in the 1915 star-making Theda Bara vehicle A Fool There Was. When Allison was cast that same year opposite actor Harold Lockwood in the Allan Dwan directed romantic film David Harum, audiences quickly became enamored of the onscreen duo and the two began a hugely successful onscreen film collaboration. Possibly the first such publicly celebrated “romantic duo” of the silver-screen, the two actors were never romantically involved offscreen. The pair starred in approximately twenty-five highly successful features together during the World War I era.

Allison and Lockwood’s highly popular film romances ended, however, when in 1918 Lockwood died at the age of 31 after contracting Spanish influenza, a deadly epidemic that swept the world from 1918 through 1919 killing 50 to 100 million people globally. Allison’s career then faltered markedly without her popular leading male co-star.  Allison continued to act in films throughout the 1920s, although she never received the same amount of public acclaim as when she starred opposite Harold Lockwood. Her last film before retiring was 1927’s The Telephone Girl opposite Madge Bellamy and Warner Baxter.

In 1920, Allison married writer and actor Robert Ellis. The couple divorced in 1923. Allison then married Photoplay magazine editor James R. Quirk, a union that lasted until 1932. Allison’s third marriage, to Carl Norton Osborne, lasted over forty years until his death in 1982. In her later years, May Allison spent much of her time at her vacation home in Tucker’s Town, Bermuda and was a Patron of the Cleveland Symphony. She died of respiratory failure in Bratenahl, Ohio in 1989 at the age of 98 and buried at the Gates Mills South Cemetery in Gates Mills, Cuyahoga County, Ohio.