It's the late 1960s and 17-year-old Susanna Kaysen (WINONA RYDER) has just tried to kill herself with an overdose of aspirin. Unsure of herself and the rapidly changing world around her, Susanna agrees to admit herself into Claymoore Hospital, a psychiatric institute for troubled young women.
There she meets head nurse Valerie (WHOOPI GOLDBERG), as well as her "Wizard of Oz" obsessed roommate, Georgina (CLEA DUVALL). She also meets Polly (ELISABETH MOSS) a young woman who previously tried to burn off half her face and Daisy (BRITTANY MURPHY), a pampered "daddy's girl" with a thing for saving rotisserie chicken carcasses under her bed.
It's Lisa (ANGELINA JOLIE), however, who most fascinates and intimidates Susanna. A charming, but rebellious delinquent, Lisa's repeatedly busted out of Claymore. Upon her latest return she teaches Susanna "the ropes" about how to survive in such an institution and deal with the psychiatrists there, including Dr. Potts (JEFFREY TAMBOR) and Dr. Wick (VANESSA REDGRAVE).
They try to make sense of Susanna's behavior that includes her promiscuous ways with Tobias Jacobs (JARED LETO), a would-be draft dodger, as well as the husband of one of her former classmates and one of the institution's orderlies.
As Susanna's friendships and deep bonds with the girls grow, she must try to sort out her sanity and place in the world, while also dealing with the increasingly volatile Lisa who may yet get her into even greater trouble.