She is the niece of Diana Barrymore and the grandniece of Lionel Barrymore, Ethel Barrymore and Helene Costello, the great-great-granddaughter of John Drew and actress Louisa Lane Drew, and the great grandniece of Broadway idol John Drew, Jr. and silent film actor, writer and director Sidney Drew.
Drew Barrymore je bila rojena v igralsko družino: njeni pra-stari starši so Maurice Barrymore in Georgie Drew Barrymore, Maurice Costello in Mae Costello (rojena Altschuk), njeni stari starši pa John Barrymore in Dolores Costello, vsi igralci; John Barrymore je bil po vsej verjetnosti najbolj priznan igralec svoje generacije.