Act One, "Fun and Games," opens at two o'clock on a Sunday morning as middle-aged couple George and Martha return home from a faculty party at a small college in the New England town of New Carthage. Over the course of the scene, as Martha bickers with George, we learn that George is a going-nowhere history professor, while Martha is the daughter of the college president. She soon informs him that she has invited a new member of the Math Department over for drinks. Martha also loudly sings, "Who's Afraid of Virginia Woolf?" a joke of a song they heard at the faculty party and is angry that George doesn't laugh. Before their guests arrive, George warns her not to do "the bit about the kid."
Their guests are Nick, a blond 30-year-old professor in the Biology Department, and his wife Honey. Nick and Honey are somewhat shocked at being thrown into the war zone that is Martha and George's marriage. While Honey copes by drinking brandy after Brandy, Nick attempts to insinuate himself into his hosts' good graces. Drunken Martha is shamelessly flirting with him immediately. Martha goes off to show Honey to the bathroom. While the women are gone, George bitterly suggests that Nick will take over the Biology Department and the college. When Honey returns, she mentions that she didn't know George and Martha had a son. George is furious at Martha, who has told Honey that their son, whose 21st birthday is tomorrow, will be returning home the next day.
Martha, who has changed into a seductive outfit, continues shamelessly flirting with Nick and insulting George, telling a story about how she punched George when he refused to join in a boxing match with her father. George grows fed up and leaves the room. He comes back with a rifle and shocks everyone by firing it at Martha. A parasol, not a bullet, erupts from the barrel. The tension dissipates a bit and George, much to Martha's chagrin, insists on talking about their son. The two argue which has been the worse influence on the boy, and Martha proceeds with her tact of humiliation by telling Nick and Honey how George is flop who failed to take over the History Department, as she'd anticipated when they got married. Their shouting match ends when George grabs Honey and dances around with her while singing "Who's Afraid of Virginia Woolf?" Honey rushes off to the bathroom to be sick.
Act Two, "Walpurgisnacht," opens as Martha is making coffee in the kitchen. George learns from Nick that he married Honey because she was pregnant with what ended up being a hysterical pregnancy. The added bonus is that she is rich, left money by her evangelist father. He half-jokingly confides his plan to rise to power at the college by sleeping with wives of important faculty members. George shares an anecdote of a boy, whom he says he knew in prep school, who ordered "bergin" at a gin joint with his friends. This boy had accidentally killed his mother with a shotgun, and a year later, with his learners permit in his pocket, he crashed into a tree and killed his father.
Martha and Honey return. Martha is even more blatant in her flirtation with Nick. When Honey declares that she wants to do Interpretive Dance, Martha takes the opportunity to dance with Nick in a blatant lascivious manner. George gets fed up when Martha continues to insult him, suggesting that the boy who ordered "bergin" and killed his parents was George and mocking his failed attempt at publishing a novel. He tries to strangle her, but Nick pulls him off.
George announces it's time for a new game. They've just finished playing Humiliate the Host, and there will be time for Hump the Hostess later. Now, it's time for Get the Guests. George toys with a confused Honey by telling her a story of a girl named Mousie who puffed up and whose puff went "poof." Honey again runs off to be sick again.
While Honey is lying on the cool tile of the bathroom floor, George turns his back to Martha and Nick, who begin to kiss and grope on the couch. Martha is annoyed that George is not paying attention and getting angry. She and Nick eventually move off to the kitchen, bumping into the doorbell chimes on the way. Honey stumbles out to the living room, still half in her dream, telling George that she heard bells. Honey's half-coherent mumblings reveal that she's terrified of having children and has actually been secretly preventing getting pregnant. Honey's continued talk of bells gives George an idea of how to get even with Martha he'll tell her he received a telegram that said that their son is dead.
Act Three, "The Exorcism," opens as Martha wanders onstage alone. Drunk and exhausted, she launches into a confused monologue which reveals her desperation and loneliness. She says that she and George cry all the time, then freeze their tears into ice cubes for their drinks. Nick comes back onstage, wondering what has happened. George is gone, and Honey is back in the bathroom. Martha calls him a flop and reveals his impotence, surprising him when she tells him that George is the only one who can satisfy her. She tells Nick not to believe appearances and praises George's ability to learn the games as quickly as she can change the rules.
Nick is furious and grows more so when Martha continually refers to him as a houseboy and a gigolo. When the doorbell starts ringing, she tells the houseboy to get it. It's George, hiding behind a bouquet of flowers, quoting a line from Tennessee Williams' A Streetcar Named Desire: "Flores para los muertos." George pretends to be a Western Union man and acts as if he's mistaken Nick for his and Martha's son. Nick gets fed up and calls them vicious, and George and Martha join together in deriding them.
Soon, George and Martha launch into another series of arguments over seemingly meaningless topics whether or not there is a moon that night, whether or not George has taken a trip to Majorca that continually reference truth and illusion. George starts throwing his bouquet of snapdragons at Martha, telling her their marriage has gone snap.
George drags Honey back into the room and announces one last game, Bringing Up Baby, to be played to the death. Honey, very drunk and holding a bottle, wants to play Peel the Label instead. George assures her they have. George begins to tell a rehearsed story about their son, scared away by Martha's overbearing presence. Martha counters with a story of her own describing an idealized childhood. During her story, George begins to chant the Requiem. In the midst of this, Honey suddenly cries out that she wants a child. Martha begins to blame George for dragging the boy down with him, and their argument intensifies. Honey pleads for them to stop.
Slowly and deliberately, George tells Martha that their son is dead. He was driving on a country road, swerved to avoid a porcupine, and crashed into a tree, the exact details of the "bergin" boy's story. Martha is furious and yells that George has no right to do this. George insists that those were always the rules of the game, and that once she broke the rules by mentioning their son, he had no other choice. Nick finally realizes that the son is imaginary, and George confirms his suspicions. They couldn't have any children. He suggests Nick and Honey go home.
The last few minutes of the play are quiet and tender. George assures Martha that things will be better and says a quiet no to her suggestion that they create another child. He begins to sing her "Who's Afraid of Virginia Woolf?" as a sort of lullaby, and Martha answers, "I am."