An eccentric heiress raises her nephew to be a free spirit.

In 1928, Edwin Dennis completes his last will and testament stating that, upon his death, his only son Patrick will be reared by his sister, Mame Dennis, under the conservative eye of banker Dwight Babcock. The day after the will is signed, Dennis drops dead and his faithful Irish servant, Norah Muldoon, takes the young Patrick from Chicago to Mame's residence at 3 Beekman Place, New York City. They arrive during a party, in which the flamboyant Mame is graciously entertaining with breezy charm and bootlegged alcohol. Among the Bohemian guests are a man and his monkey, the headmaster of a nudist school, a composer and his wife, artists of all kinds, someone who looks like Gertrude Stein and a non-English-speaking Orthodox Lithuanian bishop. Upon realizing that Patrick is her nephew, Mame invites him to join the party and he hungrily eats caviar, which he calls "fishberry jam." Afterward, Mame instructs Patrick to write down all the words he heard that he did not understand and promises that she will "open doors" that he "never dreamed existed." Two weeks and thirteen cocktail parties later, Norah and Patrick have settled into the eccentric household with Mame's houseboy, Ito, her best friend, actress Vera Charles, who sleeps off hangovers in one of Mame's extra rooms, and Mame's boyfriend, publisher Lindsay Woolsey, who also visits frequently. When Babcock arrives to check on Patrick, the well-mannered boy skillfully mixes him a martini. Babcock wants to enroll Patrick in an "exclusive and restricted" boys' school and Mame pretends to agree. Later, when Babcock learns that Patrick is enrolled at Acacius Page's experimental school in Greenwich Village, he insists on sending the boy to a boarding school, breaking the hearts of both Mame and Patrick, who have grown close. In the stock market crash of 1929, Mame loses her fortune and then breaks off with Lindsay, because she refuses to marry for security. Needing a job, she takes a small role in Vera's new play, but, unable to be inconspicuous in her tiny role, Mame ad-libs, jangles her jewelry and catches her bracelets on Vera's costume during the play's New Haven tryouts, turning the drama into comedy. Only Patrick is impressed with her performance and she is soon looking for another job. After failing as a switchboard operator, Mame takes a job as a sales clerk at Macy's department store during the pre-Christmas season. That job, too, is short-lived, because Mame can only write sales slips that are "Cash On Delivery." With no money coming in, Mame's close-knit household struggles to have a meaningful, if meager, Christmas. Norah, who finds Mame "odd, but lovin'", and Ito have stayed on without being paid and settle the butcher's bill with their own savings as a Christmas present. Soon after, oil millionaire Beauregard Jackson Pickett Burnside knocks on the door, after having seen Mame at Macy's and consequently searching the city for her. He invites them out to dinner, and later, to his Georgia plantation. Although Beauregard is captivated by Mame, his family is not, and Sally Cato McDougal, a neighbor who has failed to capture Beauregard's heart, tries to sabotage their blooming relationship. When Mame, to please Beauregard, claims untruthfully that she can ride a horse, Sally arranges a foxhunt and gives Mame an untrainable horse to ride. Although Mame has difficulty controlling the horse, at the end of the hunt, she is holding the exhausted fox and the impressed Beauregard proposes to her in front of everyone. For their honeymoon, the newlyweds embark on an extended world tour, and Patrick, now a university student, joins them during holidays. While skiing the Matterhorn, Beauregard, who is a camera buff, falls over a cliff to his death while taking a picture and the grieving Mame continues traveling alone, revisiting the places she and Beauregard had been. When she eventually returns to Beekman Place, Patrick, believing Mame needs a project, has arranged for her to write her memoirs, which Lindsay will publish. To assist Mame, Patrick hires a stenographer, timid and frumpy Agnes Gooch, to take dictation and an Irish poet, Brian O'Bannion, to serve as her editor. For the next few months, Mame dictates to Agnes, and O'Bannion lives well and does little. Unexpectedly one day, Patrick arrives, wanting Mame to meet his girl friend, Gloria Upson. Claiming that Gloria is from "good conservative stock," Patrick admits that he is ashamed of Mame's "peculiarities" and begs her to act normal when Gloria visits. Sadly, Mame realizes that Patrick has become a product of Babcock's choice of schooling: "beastly," "bourgeois" and a "snob." Although Patrick has embraced the opposite of everything she believes in, Mame loves him deeply and says she will do anything for him. As Patrick is to arrive with Gloria within the hour, Mame breaks a date to attend a party with O'Bannion and dresses up Agnes to escort him. To calm Agnes, Mame gives her a whiskey, which the frightened woman is unused to drinking, and, for courage, tells her the motto by which she lives: "Life is a banquet and most poor suckers are starving to death." When Patrick and the spoiled and shallow Gloria arrive, they tell Mame that they are already engaged. Agnes returns the next day, alone and remembering little of her adventure. Soon, Mame journeys to Connecticut to meet Gloria's family, the bigoted and gauche Claude and Doris Upson. The Upsons have planned the children's wedding, decided on Patrick's career and even ask Mame to pay for half of the cost of property adjacent to theirs for a wedding present. Mame learns that the Upsons have a double motive for choosing that particular wedding gift, as they wish to prevent a Jewish man from buying the property and moving into the neighborhood. While secretly abhorring the Upsons, Mame offers to have them come to Beekman Place for an "intimate family dinner" in the near future. A few months later, final preparations are being made for the dinner. Patrick is horrified to find Agnes several months pregnant by O'Bannion, who has not been seen since the night of the party. Patrick insists that she must go upstairs when the Upsons arrive. Upon meeting Mame's new secretary, Pegeen Ryan, who is hanging an odd-looking sculpture in Mame's newly redecorated foyer, Patrick jokes and temporarily regains his former, unpretentious charm. When Gloria, the Upsons and Babcock arrive, Mame directs them to sit in her new, avant-garde seating area that can be raised and lowered by the push of a button. For hors d'oeurves, she serves pickled rattlesnake and a flaming beverage in a martini glass, bewildering her guests as to how to drink it. Agnes waddles down to take a calcium pill, and then cries when Doris asks about her "husband." After Acacius, Vera and Lindsay arrive, Mame passes out chapters from the galleys of her book for all to read. At first Patrick is embarrassed, but soon begins to reminisce. Mistaking Pegeen for Patrick's intended, Vera toasts them. Gloria, wanting attention, tells a meaningless story that embarrasses everyone but her parents. The Upsons are shocked when Vera points out that Mame's book will be the "raciest" of the year, but are even more scandalized when they learn that Agnes is unwed. When a telegram from O'Bannion arrives, demanding money and claiming that he and Agnes are married, Mame congratulates the relieved Agnes. Offended, Gloria expresses her disapproval of Patrick's family and after Patrick calls her selfish and empty headed, she breaks off their engagement. Mame then announces that she is donating money to build a home for refugee children on the lot next to the Upsons'. Infuriated, the Upsons inadvertently cause their seats to elevate, and after disentangling themselves, leave in a huff. Babcock berates Mame for ruining his carefully laid plans for Patrick, but Mame says she could not watch her nephew be "shut in a safe-deposit box." Patrick simply thanks her and, years later, watches with his wife Pegeen as Mame lures their entranced son Michael through "open doors" he "never dreamed existed."