Barrymore was born in Los Angeles, California to John Barrymore and Dolores Costello. His parents separated when he was 18 months old, and he rarely saw his father afterward. Educated at private schools, he made his film debut at 18, billed as John Barrymore Jr. In 1958, he changed his middle name to Drew, although he had previously been credited in past works as Blyth, and appeared in many low budget films such as High School Confidential, Never Love a Stranger (1958), Night of the Quarter Moon (1959), and The Keeler Affair (1963) as Stephen Ward. This was followed by a brief resurgence in Italian movies as he appeared in several leading roles. He also appeared several times in the TV series Gunsmoke. However, Barrymore’s social behavior obstructed any professional progress. In the 1960s, he was occasionally incarcerated for drug use, public drunkenness, and spousal abuse. He guest-starred in other memorable episodes of classic TV Westerns Rawhide — “Incident of The Haunted Hills” — playing a half-Native, half-White outcast and Wagon Train — “The Ruttledge Munroe Story” — playing a “too cheerful” character who spreads death wherever he goes and turns out to be a figure from Major Adams’s (Ward Bond) military past. In 1966, Barrymore was signed to play a guest role as Lazarus in the Star Trek episode “The Alternative Factor”. However, he failed to show up (and was ultimately replaced at the last minute by actor Robert Brown), resulting in a SAG suspension of six months. He did appear as Stacey Daggart in the 1966–67 NBC series The Road West, starring Barry Sullivan.

All four of Barrymore’s marriages ended in divorce. He married actress Cara Williams in 1952; they divorced in 1959. His fourth child is film actress and producer Drew Barrymore. Although he continued to appear occasionally on screen, he became more and more reclusive. Suffering from the same problems with addiction that had destroyed his father, Barrymore became a derelict. Estranged from his family, including his children, his lifestyle continued to worsen and his physical and mental health deteriorated. In 2003, daughter Drew Barrymore moved him near her home despite their estrangement, paying his medical bills until his death from cancer. He has a star on the Hollywood Walk of Fame for his contributions to television.