Agnes Gooch brings young Patrick Dennis from a farm in Des Moines to his only living relative, Mame Dennis. This notorious Auntie Mame is a swinger; a vogue-following, high-living friend to everyone. Knowledge, love, and the stock market are her dearest possessions.
She is overjoyed with Patrick. Unfortunately her authority over him is shared with Dwight Babcock, a trustee for the Knickerbocker Bank. They clash on schooling, but Patrick's father's will spells out a conservative education. Babcock wins, but Mame is busy opening exciting windows for Patrick behind Babcock's back. Babcock catches Patrick enrolled in Ralph Devine's Laboratory of Life - a forward thinking establishment. This is hardly a conservative education as stipulated in the will and so he packs Patrick away to boarding school.
To add to her problems, the stock market has crashed and Mame must attempt the only thing in the world for which she is unsuited - work. She gets a job in the theatre in the show that her friend is starring in. However, she upstages her actress-friend, Vera Charles, and is fired.
Jobs come easy - but go just as fast. Mame is so broke the servants have paid the bills with their rainy-day money. Suddenly Santa Claus appears in the person of Beauregard Jackson Picket Burnside. It is obvious that he and Mame are a born pair. The proposal comes fast, but Mame must meet his Southern relatives.
As a prospective Yankee in the family, her reception is not the warmest. Especially from Sally Cato, who has been engaged to Beau since grammar school. Sally gets Mame to agree to go to a hunt and which has been designed to make a fool of her. But the plot backfires. Mame captures the fox alive and wins the respect of all. She and Beau are married and depart for an around-the world honeymoon.
Patrick is now in college and is pursuing love interests of his own.
Several years into the honeymoon Beau slips from the Matterhorn and is killed. Mame returns to her old friends and is persuaded to write her memoirs.
During her absence Patrick has joined Junior Babcock's circle of friends and is engaged to Gloria Upson. Mame is invited to the country to meet the family, plus their kitsch taste and public prejudices. The Upsons have everything planned, including a buy-up of the unrestricted land next to theirs on which the kids will build a house and thereby keep away the riff-raff. Mame is stunned and asks Patrick how he can put up with such bigotry. Unkind words are aired, and both are hurt. However, Mame has designed an engagement party of her own. The Upsons and Babcock arrive and the event is typical Mame. Her friends drop in, leaving the guests aghast. Pregnant Agnes shows up and admits she's not married. Mame uses the shocked silence to announce that she has purchased the country homesite to establish the Burnside Memorial Home for Single Mothers. The guests storm out. Their poor behaviour is enough for Patrick to realize his mistakes. He and Mame are reunited.
Decorator Pegeen Ryan, who has been putting the final touches on Mame's apartment during the progress of the party, has caught Patrick's eye. As Mame had suspected, they make a perfect couple and at curtain she's off to India with Stephen, their 10-year old son, to help him open the windows of the world!