Born in Scranton, Pennsylvania, after attending Yale University, Endfield began his career as a theatre director and drama coach, becoming an important figure in New York's progressive theatre scene. Despite this shared background, it was largely Endfield's skill as a card magician which brought him to the attention of Orson Welles, who recruited him as an apprentice for Mercury Productions (at that time based at RKO Pictures). Following the debacle surrounding the production of The Magnificent Ambersons (which ended with the expulsion of the Mercury team from the RKO lot) Endfield signed on as a contract director at MGM, directing a wide variety of shorts (including the last films in the long-running Our Gang series), before moving on to freelance on low-budget productions for Monogram and independents.

It was with the 1950 film noir The Underworld Story, an independent production released through United Artists, that Endfield first came to critical and studio attention. The film was a major leap from anything he had produced before in terms of budget and social commentary, a coruscating attack on press corruption which could equally be taken as a wider attack on the McCarthyite ideology of the times. He followed this with the film often cited as his masterpiece, The Sound of Fury (aka Try And Get Me!), a lynching thriller based on a true story. It was with these two films that Endfield's signature approach to character developed, pessimistic without being uncompassionate.

In 1951 Endfield was named as a Communist at a HUAC hearing. Blacklisted by the movie studio bosses, he was unable to get work in Hollywood and moved to Britain where he wrote and directed films under various pseudonyms, often starring fellow blacklistees. In 1958, Endfield was nominated for a BAFTA Award for Best British Screenplay for Hell Drivers. In 1961 he made Mysterious Island featuring special effects by Ray Harryhausen. His most famous work is 1964's Zulu. After a few more independent productions he withdraw from film direction in 1971. In 1979 he wrote the non-fiction book Zulu Dawn, which tells the story of the British military campaign against the Zulu Nation in 1879. A film adaptation of the book was released in the same year, co-written by Endfield and directed by Douglas Hickox.

Cy Endfield died in 1995 in Shipston-on-Stour, Warwickshire, England, UK.