In Chicago during the early 1930s, McNeill was assigned to take over an unsponsored early morning variety show, The Pepper Pot, with an 8 a.m. timeslot on the NBC Blue Network. McNeill re-organized the hour as The Breakfast Club, dividing it into four segments which McNeill labeled "the Four Calls to Breakfast."

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McNeill's revamped show premiered in 1933, combining music with informal talk and jokes often based on topical events, initially scripted by McNeill but later ad-libbed. In addition to recurring comedy performers, various vocal groups and soloists, listeners heard sentimental verse, conversations with members of the studio audience and a silent moment of prayer. The series eventually gained a sponsor in the Chicago-based meat packer Swift and Company, beginning February 8, 1941. McNeill is credited as the first performer to make morning talk and variety a viable radio format.

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The program featured Fran Allison (later of Kukla, Fran and Ollie fame) as "Aunt Fanny", plus Captain Stubby and the Buccaneers and various comedy bits. Every quarter-hour came the "Call to Breakfast"—a march around the breakfast table. A featured vocalist on the show, under her professional name of Annette King, was Charlotte Thompson Reid, who later became an Illinois congresswoman for five terms (1962–71). Eileen Parker became a vocalist with the program in 1953.

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The Breakfast Club initially was broadcast from the NBC studios in the Merchandise Mart. In 1948, after 4,500 broadcasts from the Merchandise Mart, the program moved to the new ABC Civic Studio. It was also heard from other Chicago venues: the Terrace Casino (at the Morrison Hotel), the College Inn Porterhouse (at the Sherman House) and "the Tiptop Room of the Warwick Allerton Hotel on Chicago's Magnificent Mile," as well as tour broadcasts from other locations in the U.S. It remained a fixture on the ABC radio network (formerly the NBC Blue Network; it became known as ABC in 1945), maintaining its popularity for years and counting among its fans Supreme Court Associate Justice William O. Douglas.

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After ABC Radio was split into four networks in 1968, The Breakfast Club was moved to the new American Entertainment network, and was known for its last months on the air as The Don McNeill Show.