The musical revolves around the antics of Mame Dennis (Lucille Ball), a fun-loving, wealthy eccentric with a flare for life and a razor sharp wit. Her life is suddenly changed when she becomes the guardian of her late brother's only child, Patrick Dennis. Her adventures take us from the speak-easies of the roaring 20's to the depression following the great Stock Market crash. She is rescued by a wealthy Southern plantation owner (Robert Preston), marries and is widowed suddenly, and through it all, manages to keep things under control. With some help from her dearest friend, Vera Charles (Bea Arthur), she helps keep things at 3 Beekman Place a rousing free-for-all.

Wealthy, eccentric Mame Dennis is living it up during the Roaring 20's when she becomes guardian to her late brother's little boy Patrick. She embraces the new role with typical enthusiasm, showing her charge how to live to the fullest, filling his life with culture, adventure, and fun. Mame and Patrick go through good times and bad during his childhood. But when he returns home from college and Mame in introduced to his stuffy fiance and bigoted parents, she faces her greatest challenge.