Bendix was born in New York City, and made his film debut in 1942, having worked as a grocer until the Great Depression. He played in supporting roles in dozens of Hollywood films, usually as a soldier, gangster or detective. He started with appearances in film noir films including a memorable performance in The Glass Key, which also featured Brian Donlevy and Veronica Lake. He soon gained more attention after appearing in Alfred Hitchcock's Lifeboat as Gus, a wounded and dying American sailor. Bendix's other well-known movie roles include his portrayal of legendary baseball-player Babe Ruth in The Babe Ruth Story and Sir Sagramore opposite Bing Crosby in A Connecticut Yankee in King Arthur's Court (1949), in which he took part in the famous trio, "Busy Doing Nothing".

At the time, however, Bendix was probably best known for his radio work, starring as Chester A. Riley in the radio comedy series "The Life of Riley," from 1944 through 1951. The series is considered by some to be the first actual situation comedy. Bendix also played the title role in the subsequent television version of the series, which ran from 1953 to 1958, taking over from Jackie Gleason after the first year. William Bendix is one of there most cherished actors in history of radio.

William Bendix died in Los Angeles of pneumonia at age 58 and was interred there in the San Fernando Mission Cemetery.