She was the sister of actors John Barrymore and Lionel Barrymore, the aunt of actor John Drew Barrymore, and the great-aunt of actress Drew Barrymore. She was also the niece of Broadway matinée idol John Drew Jr and early Vitagraph movie star Sidney Drew.
Her first appearance in Broadway was in 1895, in a play called The Imprudent Young Couple which starred her uncle John Drew Jr and Maude Adams. She appeared with Drew and Adams again in 1896 in Rosemary. She portrayed Nora in A Doll's House by Ibsen (1905), and Juliet in Romeo and Juliet by Shakespeare (1922).
She was also a strong supporter of the Actors' Equity Association and had a high-profile role in the 1919 strike. In 1926, she scored one of her greatest successes as the sophisticated spouse of a philandering husband in W. Somerset Maugham's comedy, The Constant Wife. In July 1934 she starred in the play Laura Garnett, by Leslie and Sewell Stokes, at Dobbs Ferry, New York State.
Barrymore was a baseball and boxing fan. Her admiration for boxing ended when she witnessed as a spectator the brutality of the July 4, 1919 Dempsey/Willard fight in which Dempsey broke Willard's jaw and knocked out several of his teeth. Ethel vowed never to attend another boxing match.
She made her first motion picture in 1914 and in the 1940s, she moved to Hollywood, California and started working in motion pictures. The only two films that featured all three siblings, Ethel, John and Lionel Barrymore, were National Red Cross Pageant (1917) and Rasputin and the Empress (1932).
She won the Oscar for Best Supporting Actress for her role in the 1944 film None but the Lonely Heart opposite Cary Grant, but made plain that she was not overly impressed by it. On March 22 2007, her Oscar was offered for sale on eBay.
She made such other classic films as The Spiral Staircase (1946) directed by Robert Siodmak, The Paradine Case (1947) directed by Alfred Hitchcock, Portrait of Jennie (1948), Pinky (1949), and Kind Lady (1951). Her last film appearance was in Johnny Trouble (1957). She also made a number of television appearances in the 1950s.
Winston Churchill proposed to her around 1900, but she turned him down. Ethel married Russell Griswold Colt (1883–1959) on March 14 1909. The couple had been introduced by her brother John. The couple had three children: actress/singer Ethel Barrymore Colt (1912–1977), who appeared on Broadway in Stephen Sondheim's Follies; Samuel Colt (1909-1986); and John Drew Colt (1913–1975). They divorced in 1923. A devout Roman Catholic, she never remarried though she had relationships with other men most notably actors Henry Daniell and Louis Calhern.