Miriam “Midge” Maisel is an upper middle class Jewish housewife living on the Upper West Side of Manhattan in 1958. Her husband, Joel, is a businessman who moonlights as a struggling comedian at The Gaslight Cafe.

One night, after a particularly unsuccessful performance as a stand-up comedian, Joel confesses to Midge that he has been having an affair with his secretary, and leaves her. Devastated when her husband walks out, with her powder-blue suitcase, Midge gets drunk and returns to the Gaslight Cafe. She impulsively goes on stage, delivering an impromptu set, confessing her predicament to the audience. Her bawdy, biting and brilliant delivery enthralls the audience. She gets so carried away describing her misfortune, that she partly strips, after which she is promptly arrested. She is hauled off to jail with the not-yet famous, iconic comic, Lenny Bruce. After she bails him out of jail, Bruce warns Midge that the comedy business is terrible, but Midge takes his warning as encouragement and teams up with Susie Meyerson, Gaslight Cafe comedy club employee and comic manager wannabe, to hone her act. Susie encourages Midge to push herself to become a professional stand-up comedienne, although Midge at first is not so sure.