The daughter of the actors Maurice (Barrymore, Maurice) and Georgiana Drew Barrymore (Barrymore, Georgiana), Ethel made her professional debut in New York City in 1894 in a company headed by her grandmother, Louisa Lane Drew (Drew, Louisa Lane). Barrymore scored her first success in London in The Bells and Peter the Great (1897–98). She starred for the first time on Broadway in Captain Jinks of the Horse Marines (1901).

Barrymore's notable plays include Alice-Sit-by-the-Fire (1905), Mid-Channel (1910), Trelawny of the “Wells” (1911), Déclassée (1919), The Second Mrs. Tanqueray (1924), The Constant Wife (1928), Scarlet Sister Mary (1931), Whiteoaks (1938), and The Corn Is Green (1942). In 1928 she opened the Ethel Barrymore Theater in New York, named in her honour, with The Kingdom of God.

Barrymore also appeared in vaudeville, on radio, and on television and made several motion pictures. She and her brothers, John (Barrymore, John) and Lionel Barrymore (Barrymore, Lionel), recognized the potential of that new medium, film, though Ethel never took easily to the screen. She made her film debut in The Nightingale (1914) and appeared in films made in New York and Hollywood through 1919. But she never cared for Hollywood, or for working in films, and so she returned to New York City and the stage.

During the 1920s and '30s she made only one film, Rasputin and the Empress (1933), which was the sole work in which she appeared with her brothers. In 1944 Clifford Odets (Odets, Clifford) convinced her to play an impoverished cockney mother opposite Cary Grant (Grant, Cary) in the film None but the Lonely Heart. For that performance, she effectively toned down her performing style and received an Academy Award for best supporting actress. She again gave a compassionate performance in The Spiral Staircase (1946) and finally seemed comfortable making movies. In her later films she was usually cast as an imperious but lovable matriarch. Her memoir, Memories, an Autobiography, was published in 1955.