San Antonio Rose is an amiably wacky mini-musical evenly divided between its "official" stars, The Merry Macs, and a strong cast of supporting clowns. Robert Paige plays roadhouse operator Con Conway, whose establishment is in danger of being squeezed out by its competition. Stranded entertainers Hope Holloway (Jane Frazee) and Gabby Trent (Eve Arden) decide to revivify Conway's establishment by staging an energetic floor show built around the talented Merry Macs. A rival club owner dispatches his two top hooligans Jigsaw Kennedy (Lon Chaney Jr.) and Benny the Bounce (Shemp Howard) to wreck Conway's club by posing as waiters, but the two stupes are easily cowed into submission--by the leading ladies!

Elmer Whippet inherits the Whippet Pickles company and sets out to meet the two stars, Mary Reynolds and John Stowe, of the radio program sponsored by his company, as he thinks their on-air quarreling is real. Two former associates, Jules Kinsey and J.M. Snow cross him up by substituting Susan Blair, an office secretary, for Mary and Elmer thinks the show's writer Paul Stevens is John.