McNeill was born in Galena, Illinois, but the family soon moved to Wisconsin, where McNeill graduated from Marquette University in Milwaukee. He was a first cousin of United States Secretary of Defense Caspar Weinberger, for their mothers were sisters. McNeill began his radio career in Milwaukee in 1928, first as a script editor and announcer at station WISN, and later working for the station owned by The Milwaukee Journal. McNeill moved on to Kentucky, working for the Louisville Courier-Journal's station, WHAS then a stint in San Francisco as a comedy act with singer Van Fleming, called "The Two Professors," and finally, following a failed career move to New York City, McNeill wound up back in Illinois in 1933.
McNeill had applied for a job at NBC, and sent to Chicago to audition. He was assigned to take over an unsponsored early morning variety show called The Pepper Pot, with an 8 AM time slot on the NBC Blue Network (later to become ABC radio). McNeill quickly re-organized the hour show as The Breakfast Club, dividing it into four segments, or as McNeill called them, "the four calls to breakfast."
The show premiered on June 23, 1933, with informal talk and jokes often based on topical events, initially scripted by McNeill, but later performed off the cuff, often with audience interviews. In its final form, this was surrounded by piano music, various vocal groups and soloists, sentimental verse, and recurring comedy performers. The series would eventually gain a sponsor, Swift and Company. McNeill was also credited as the first performer to make morning talk and variety a viable format in radio. (Countless local shows, to this day, often refer to themselves as The Breakfast Club).
McNeill briefly attempted to transfer the series to television, as Don McNeill's TV Club (1950-1951). The Breakfast Club was simulcast on television in 1954-1955. McNeill also appeared occasionally on game shows and the like, and in 1963, he hosted the short-lived game show Take Two, built around photo comparisons.
McNeill's radio series continued through this time, finally ending in 1968, at which point McNeill retired from entertainment, and from public life. McNeill's Breakfast Club was inducted into the Radio Hall of Fame in 1989, and he died seven years later, age of 88.