In 1936, he settled in Hollywood and, after playing a series of college-aged parts, began a long stint playing weaklings or sadistic losers and hoods. His acting career spanned over sixty years. Cook's characters usually ended up being killed off (strangled, poisoned or shot); he was arguably Hollywood's most notable fall guy for many years. He made a rare appearance in slapstick comedy in the cameo role of The Screenwriter (another of Cook's shy anti-heroes) in Hellzapoppin', 1941. In Universal's Phantom Lady, he portrays a slimy, intoxicated nightclub-orchestra drummer. Other notable roles include Wilmer the "gunsel" in The Maltese Falcon (1941), "pug ugly" Marty Waterman in Born to Kill, Harry Jones in The Big Sleep (1946), Torrey in Shane (1953), and George Peatty, the hen-pecked husband to Marie Windsor, in Stanley Kubrick's The Killing (1956).
Cook played a private detective in a 1953 episode of Adventures of Superman TV series entitled Semi-Private Eye. In the series DVD commentary, Jack Larson describes this as his favorite episode, both for being allowed to play a self-styled Humphrey Bogart-style shamus, and for the chance to work with "Cookie", who became a good friend. He played lawyer Samuel T. Cogley on in the Star Trek episode "Court Martial", and later had a long-term recurring role as Icepick on Magnum, P.I..
He married twice, first to Mary Lou Cook between 1929 and 1942. After they divorced, he was married to Peggy McKenna Cook from 1944 until his death. He had no children, although he spent time raising a niece. He lived in Bishop, California, typically summering on Lake Sabrina in the Sierra Nevada Mountains, and died on May 18, 1995 in Big Pine, California.
His ashes were scattered somewhere after his cremation.