Barrymore was born into acting: all of her paternal great-grandparents - Maurice Barrymore and Georgie Drew Barrymore, and Maurice Costello and Mae Costello ( Altschuk) - as well as her paternal grandparents, John Barrymore and Dolores Costello, were actors; John Barrymore was arguably the most acclaimed actor of his generation.
Po očetovi strani ima tudi polbrata po imenu John Blyth Barrymore, ki se je tudi sam uveljavil v igralski industriji, in dve polsestri: Blyth Dolores Barrymore in Brahmo "Jessico" Blyth Barrymore.