Bendix, named william after his paternal grandfather, was born in Manhattan, the only child of Oscar and Hilda (Carnell) Bendix. His uncle was Composer, Conductor, and Violinist Max Bendix. In the early 1920s, Bendix was a batboy for the New York Yankees and said he saw Babe Ruth hit more than a hundred home runs at Yankee Stadium. However, he was fired after fulfilling Ruth's request for a large order of hot dogs and soda before a game, which resulted in Ruth being unable to play that day. In 1927, Bendix married Theresa Stefanotti. He worked as a grocer until the Great Depression.

It was Bendix's appearance in the Hal Roach-produced film The McGuerins from Brooklyn (1942), playing a rugged blue-collar man, that led to his best remembered role. Producer and creator Irving Brecher saw Bendix as the perfect personification of Chester A. Riley, giving a second chance to a show whose audition failed when the sponsor spurned Groucho Marx for the lead. With Bendix stumbling, bumbling, and skating almost perpetually on thin ice, stretching the patience of his otherwise loving wife and children, The Life of Riley was a radio hit from 1944 through 1951, and Bendix brought an adaptation of the film version to Lux Radio Theatre.

Bendix was a Republican. In the 1944 presidential election, for instance, he attended the massive rally organized by David O. Selznick in the Los Angeles Coliseum in support of the Dewey-Bricker ticket as well as Governor Earl Warren of California, who would become Dewey's running mate in 1948 and later the Chief Justice of the United States. The gathering drew 93,000, with Cecil B. DeMille as the master of ceremonies and with short speeches by Hedda Hopper and Walt Disney. Among the others in attendance were Ann Sothern, Ginger Rogers, Randolph Scott, Adolphe Menjou, Gary Cooper, Edward Arnold, Lionel Barrymore, Leo Carrillo, and Walter Pidgeon.

Bendix's other well-known movie roles include his portrayal of Babe Ruth in The Babe Ruth Story (1948) – a film roundly considered one of the worst Sports biopics in film history and Sir Sagramore opposite Bing Crosby in A Connecticut Yankee in King Arthur's Court (1949), in which he took part in the trio, "Busy Doing Nothing". He played Nick the bartender in the film version of william Saroyan's The Time of Your Life (1948) starring James Cagney. Bendix had appeared in the stage version, but in the role of Officer Krupp (a role played on film by Broderick Crawford). He was also cast in The Blue Dahlia (1946), appearing for the second time alongside Ladd and Lake.

Bendix was not able to play the role on television because of a contracted film commitment. The part instead went to Jackie Gleason and aired a single season beginning in October 1949. Despite winning an Emmy award, the show was cancelled, in part because Gleason was less acceptable as Riley, since Bendix had been so identified with the part on radio. In 1953, Bendix became available for a new television version, and this time the show was a hit. The second television version of The Life of Riley ran from 1953 to 1958, long enough for Riley to become a grandfather. On the 1952 television program This Is Your Life, hosted by Ralph Edwards, Bendix was claimed to be a descendant of the 19th century Composer Felix Mendelssohn.

In NBC's Wagon Train ("Around the Horn", 1958), Bendix played the captain of a sailing cargo ship who shanghaied Major Adams (Ward Bond), Bill Hawks (Terry Wilson) and Charlie Wooster (Frank McGrath), forcing them to work on his ship. On November 16, 1959, Bendix appeared on NBC's color broadcast of The Steve Allen Plymouth Show with Jack Kerouac. A color videotape of the broadcast survives. Bendix starred in all seventeen episodes of the NBC western series Overland Trail (1960) in the role of Frederick Thomas "Fred" Kelly, the crusty superintendent of the Overland Stage Company. Doug McClure, later Trampas on NBC's The Virginian, co-starred as his young understudy, Frank "Flip" Flippen. He guest-starred in an episode of Mister Ed ("Pine Lake Lodge", 1961) which served as a back door pilot for a proposed sitcom that was not picked up.

Bendix died in Los Angeles in 1964, the result of a chronic stomach ailment that brought on malnutrition and ultimately lobar pneumonia. He was interred at the San Fernando Mission Cemetery, in Mission Hills, Los Angeles.

The show began as a proposed Groucho Marx radio series, The Flotsam Family, but the sponsor balked at what would have been essentially a straight head-of-household role for the Comedian. Then creator and Producer Irving Brecher saw Bendix as taxicab company owner Tim McGuerin in The McGuerins from Brooklyn. Brecher stated, "He was a Brooklyn guy and there was something about him. I thought, This guy could play it. He'd made a few films, like Lifeboat, but he was not a name. So I took The Flotsam Family script, revised it, made it a Brooklyn Family, took out the flippancies and made it more meat-and-potatoes, and thought of a new title, The Life of Riley. Bendix's delivery and the spin he put on his lines made it work." The reworked script cast Bendix as blundering Chester A. Riley, a wing riveter at the fictional Cunningham Aircraft plant in California. His frequent exclamation of indignation—"What a revoltin' development this is!"—became one of the catchphrases of the 1940s. It was later reused by Benjamin J. Grimm of the Fantastic Four.