She first appeared in New York at the Belasco Theatre in the 1910 hit comedy The Concert, which was Leo Ditrichstein's adaptation of the stage play, in which the 20-year-old actress portrayed the 76-year-old Edith Gordon.

Witherspoon appeared with Ditrichstein in September 1913 for a four-month run at the Belasco and briefly the Theatre Republic playing Fanny Lamont in The Temperamental Journey, from the comedy Pour Vivre Heureux by André Rivoire and Yves Mirandeis.

[7][9] Witherspoon had a long run between November 1915 and June 1916 at the Longacre Theatre as Mrs. Van Ness in The Great Lover, another play by Ditrichstein, written in collaboration with Fanny and Frederic Hatton.

[10] She remained active on stage for another three decades often in long-running Broadway plays, such as:[7][9] Her first film appearance was a small role in the 1931 motion picture Tarnished Lady starring Tallulah Bankhead.

Witherspoon played Mrs. Burns Norville in Libeled Lady with Jean Harlow and William Powell; Nesta Pett in Piccadilly Jim; Nora in Madame X; Patty in Quality Street; Countess de Noailles in Marie Antoinette; Carrie in Dark Victory; Mrs. Van Adams in The Women; Susie Watson in Charlie Chan's Murder Cruise; and Mrs. Williamson in The Mating Season.