Reluctant to follow his parents' career, Barrymore appeared together with his grandmother Louisa Lane Drew on tour and in a stage production of The Rivals at the age of 15. When Harlow died in 1937, Barrymore and Clark Gable mourned her as though she had been family. Years later, Barrymore developed a fatherly affection for Jean Harlow, who was born about the same time as his daughters. Barrymore never truly recovered from the deaths of his girls, and their loss undoubtedly strained his marriage to Doris Rankin, which ended in 1923. Doris Rankin bore Lionel two daughters, Ethel Barrymore II (1908 – 1910) and Mary Barrymore (1916 – 1917). Doris's sister Gladys was married to Lionel's uncle Sidney Drew, which made Gladys both his aunt and sister-in-law. He was married twice, to actresses Doris Rankin and Irene Fenwick, a one-time lover of his brother, John. Barrymore graduated from Seton Hall Preparatory School, the Roman Catholic college prep school, in the class of 1891. While raised a Roman Catholic, Barrymore attended the Episcopal Academy in Philadelphia. He attended private schools as a child, including the Art Students League of New York. He was the elder brother of Ethel and John Barrymore, the uncle of John Drew Barrymore and Diana Barrymore and the great-uncle of Drew Barrymore, among other members of the Barrymore family.
Lionel Barrymore was born Lionel Herbert Blythe in Philadelphia, the son of actors Georgiana Drew Barrymore and Maurice Barrymore (born Herbert Arthur Chamberlayne Blythe).