The first Life of Riley radio show was a summer replacement show heard on CBS from April 12, 1941 to September 6, 1941. The CBS program starred Lionel Stander as J. Riley Farnsworth and had no real connection with the more famous series that followed a few years later.

The radio program starring William Bendix as Riley initially aired on the Blue Network, later known as ABC, from January 16, 1944 to June 8, 1945. Then it moved to NBC, where it was broadcast from September 8, 1945 to June 29, 1951.

The supporting cast featured Paula Winslowe portraying Peg, Riley's wife, as well as playing Riley's Mother-in law, John Brown, who portrayed not only undertaker "Digger" O'Dell but also Riley's co-worker Jim Gillis, Francis "Dink" Trout played the character of Waldo Binny, Tommy Cook, Bobby Ellis and Scotty Beckett each played the role of Junior during the show's run, Sharon Douglas played Babs, and in one episode Henry Morgan voiced Riley's father. Alan Reed was a regular on the show in multiple characters, from Riley's boss Mr. Stevenson to Peg's father, Shirley Mitchell played Honeybee Gillis and Hans Conried was Uncle Baxter.

Whereas Gillis gave Riley bad information that got him into trouble, Digger gave him good information that "helped him out of a hole", as he might have put it. Brown's lines as the undertaker were often repetitive, including puns based on his profession; but, thanks to Brown's delivery, the audience loved him. The program was broadcast live with a studio audience, most of whom were not aware Brown played both characters. As a result, when Digger delivered his first line, it was usually greeted with howls of laughter and applause from surprised audience members.

The series was co-developed by the non-performing Marx Brother turned agent, Gummo. The American Meat Institute (1944–45), Procter & Gamble (Teel dentifrice and Prell shampoo) (1945–49), and Pabst Blue Ribbon beer (1949–51) took turns as the radio program's sponsor.