In 1884 she, her parents and brothers sailed to England and stayed two years. Maurice had inherited a substantial amount of money from an aunt and decided to exhibit a play and star in some plays at London's Haymarket Theatre. Ethel recalled being frightened on first meeting Oscar Wilde when handing him some cakes and later being reprimanded by her parents for showing fear of Wilde. Returning to the U.S. in 1886, her Father took her to her first baseball game. She established a lifelong love of baseball and wanted to be a concert Pianist. The years in England were the happiest of her childhood years due to the fact the Barrymores were more of a nuclear family in London than at any other time when in the United States.

In the summer of 1893 Barrymore was in the company of her mother, Georgie, who had been ailing from tuberculosis and took a sabbatical for a cure to Santa Barbara, California not far from where family friend Helena Modjeska had a retreat. Georgie did not recover and died in July 1893 a week before her 37th birthday. Essentially Ethel and Lionel's childhood ended when Georgie died; they were forced to go to work in their teens with neither finishing high school. John, a few years younger, stayed with their grandmother and other relatives. Barrymore's first appearance on 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.

In 1897 Ethel went with william Gillette to London to play Miss Kittridge in Gillette's Secret Service. She was about to return to the States with Gillette's troupe when Henry Irving and Ellen Terry offered her the role of Annette in The Bells. A full London tour was on and, before it was over, Ethel created, on New Years Day 1898, Euphrosine in Peter the Great at the Lyceum, the play having been written by Irving's son, Laurence. Men everywhere were smitten with Ethel, most notably Winston Churchill, who asked her to marry him. Not wishing to be a politician's wife, she refused. Winston, years later, married Clementine Hozier, a ravishing beauty who looked very much like Ethel. Winston and Ethel remained friends until the end of her life. Their “romance” was their own little secret until his son let the cat out of the bag 63 years after it happened.

Winston Churchill was among many Barrymore's new friends in England. Churchill reportedly proposed to her in 1900; Barrymore mentions no such thing in her autobiography, though she includes a photograph of herself and Churchill on the lawn at Blenheim Palace in 1899. While touring in England at age nineteen, she had been rumored to be engaged to the Duke of Manchester, actor Gerald du Maurier and Writer Richard Harding Davis and the aforementioned Churchill. Upon her engagement to Laurence Irving, son of Sir Henry Irving, an old friend of Mrs. John Drew, she cabled her Father Maurice, who responded with a cable "Congratulations!". When she broke up with Irving, she cabled Maurice who wired back, "Congratulations!".

After her season in London, Ethel returned to the U.S. Charles Frohman cast her first in Catherine and then as Stella de Grex in His Excellency the Governor. After that, Frohman finally gave Ethel the role that would make her a star: Madame Trentoni in Captain Jinks of the Horse Marines, which opened at the Garrick Theatre in London's West End on February 4, 1901. Unbeknownst to Ethel, her Father Maurice had witnessed the performance as an audience member and walked up to his daughter, congratulated her and gave her a big hug. It was the first and only time he saw her on stage professionally. When the tour concluded in Boston in June, she had out-drawn two of the most prominent actresses of her day, Mrs. Patrick Campbell and Minnie Maddern Fiske.

She portrayed Nora in A Doll's House by Ibsen (1905), and Juliet in Romeo and Juliet by Shakespeare (1922).

The couple had three children: Samuel "Sammy" Colt (1909–1986), a Hollywood agent and occasional actor; actress/singer Ethel Barrymore Colt (1912–1977), who appeared on Broadway in Stephen Sondheim's Follies; and John Drew Colt (1913–1975), who became an actor.

Barrymore's marriage to Colt was precarious from the start, with Barrymore filing divorce papers as early in the marriage as 1911, much to Colt's surprise, and later recanted by Barrymore as a misunderstanding by the press. At least one source alleged Colt abused her and that he fathered a child with another woman while married to Barrymore. They divorced in 1923. Barrymore did not seek alimony from Colt for herself, which was her right, but she demanded that his entailed wealth provide for their children. A devout Catholic, Ethel Barrymore never remarried.

Barrymore appeared in her first feature motion picture, The Nightingale, in 1914. Members of her family were already in pictures; uncle Sidney Drew, his wife Gladys Rankin and Lionel had entered films in 1911 and John made his first feature in 1913 after having debuted in Lubin short films in 1912. She made 15 silent pictures between 1914 and 1919, most of them for the Metro Pictures studio. Most of these pictures were made on the East Coast, as her Broadway career and children came first. A few of her silent films have survived for Example one reel from The Awakening of Helena Richie (1916) which survives at the Library of Congress and The Call of Her People (1917) held at George Eastman House.

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, though she would later watch boxing on television.

In 1928, the Shuberts opened the Ethel Barrymore Theatre, which operates under that name to the present day.

Barrymore starred in Miss Hattie, described as "a short-lived situation comedy," on ABC in 1944-1945. In one episode, Barrymore's character was "asked by Rob Thompson to direct a play which the workers of his war plant are presenting in order to raise money for war bonds."

She appeared in The Spiral Staircase (1946) directed by Robert Siodmak, The Paradine Case (1947) directed by Alfred Hitchcock, Portrait of Jennie (1948), and “The Red Danube” (1949), among others. Her last film appearance was in Johnny Trouble (1957).

Barrymore appeared in the Academy Award nominated film Pinky (1949), for which she was awarded an Academy Award nomination for Best Supporting Actress.

Barrymore also made a number of television appearances in the 1950s, including one memorable encounter with Comedian Jimmy Durante on NBC's All Star Revue on December 1, 1951, which is preserved on a kinescope. In 1956, she hosted 14 episodes of a TV series Ethel Barrymore Theatre, produced by the DuMont Television Network and presented on the DuMont flagship station WABD just as the network was folding. Unfortunately none of the episodes were preserved on kinescope. A 1952 appearance on What's My Line? survives, however, in addition to several radio broadcasts.

Ethel Barrymore died of cardiovascular disease in 1959, at her home in Hollywood, after having lived for many years with a heart condition. She was less than two months shy of her 80th birthday. She was entombed at Calvary Cemetery. The Ethel Barrymore Theatre in New York City is named for her. Barrymore was a member of the American Theater Hall of Fame, along with her brothers, John and Lionel.

In 1960, Barrymore was posthumously inducted into the Hollywood Walk of Fame with a motion pictures star for her contributions to the film industry. Her star is located at 7001 Hollywood Boulevard.

In the romantic time travel film, Somewhere in Time (1980), a photo of Barrymore wearing nun's habit from her 1928 play The Kingdom of God can be seen. Christopher Reeve plays a Journalist rummaging through old theater albums at a large Michigan hotel. He uncovers the photos of Barrymore in the play and childhood photos of actresses Blanche Ring and Rose Stahl.

The only two films that featured all three siblings—Ethel, John and Lionel—were National Red Cross Pageant (1917) and Rasputin and the Empress (1932). The former film is now considered a lost film.

Barrymore was born Ethel Mae Blythe in Philadelphia, the second child of the actors Maurice Barrymore (whose real name was Herbert Blythe) and Georgiana Drew. Her Father was nearly killed four months before her birth in a famous Old West encounter in Texas while heading a traveling road company. She was named for her father’s favorite character—Ethel in william Makepeace Thackeray’s The Newcomes.