Set in the late 1960s, Go Ask Alice is the story of an unnamed diarist whose journals show her journey through a pill addiction. The novel's tumultuous course follows the nameless girl through a flight from home, a harrowing and mentally scarring stay in an asylum, and a slide into heroin use during which she is brutally raped. Although the diarist makes heroic efforts to throw off her addiction, in the end she dies of an overdose.
A 14-year-old girl begins keeping a diary. With a sensitive, observant style, she records her thoughts and concerns about issues such as crushes, weight loss, sexuality, social acceptance, and difficulty relating to her parents.
The diarist's father, a college professor, accepts a teaching position at a new college. The diarist is at first optimistic about the move, but after it feels like an outcast at the new school, with no friends. She then meets Beth and they become best friends. When Beth leaves for summer camp the diarist returns to her hometown to stay with her grandparents. She reunites with an old school acquaintance, Jill, who is impressed by the diarist's move to a larger town, and invites her to a party. There, glasses of soda—some of which are laced with LSD—are served. The diarist unwittingly ingests LSD and has an intense and pleasurable trip.
Over the following days the diarist continues friendships with the people from the party and willingly uses more drugs. She loses her virginity while on LSD. She worries she may be pregnant, and her grandfather has a small heart attack. These events and the tremendous amount of guilt she feels begin to overwhelm her. She begins to take sleeping pills stolen from her grandparents. On returning home she receives sleeping pills from her doctor. When those are not enough she demands powerful tranquilizers from her doctor. The friendship with Beth ends as both girls have moved in new directions.
The diarist meets a hip girl, Chris, while shopping at a local boutique. The diarist and Chris become fast friends, using drugs frequently. They date college boys Richie and Ted, who deal drugs. Chris and the diarist begin selling drugs for the boyfriends, passing back all the money made. When they find the boys stoned and having sex they realize Richie and Ted were using them to make money, turn them in to the police, and flee to San Francisco. They vow to abstain from drugs. Chris secures a job in a boutique with a glamorous older woman, Shelia [sic]. The diarist gets a job with a custom jeweler whom she sees as a father figure.
Shelia invites the girls to lavish parties where they resume taking drugs. One night Shelia and her new boyfriend introduce the girls to heroin and rape them while they are stoned. The diarist and Chris, traumatized, move to Berkeley where they open a jewelry shop. It is a small success, but the diarist misses her family. Tired of the shop, the girls return home for a happy Christmas.
Returning home, the diarist encounters social pressure and hostility from her former friends from the drug scene. She and her family are threatened and shunned at times. Chris and the diarist try to stay away from drugs but their resolve lapses. The diarist gets high one night and runs away. She drifts through homelessness, prostitution, hitchhiking, and homeless shelters, before a priest reunites her with her family. She returns home, but encounters continued hostility from her former friends. They eventually drug the diarist against her will; she has a bad trip and is sent to an insane asylum. There she bonds with a younger girl named Babbie. Chris and her family move to a new town.
Released from the asylum, the diarist returns home and finally is free of drugs. She becomes romantically involved with a student from her father's college, Joel. Relationships with her family are improving, as are friendships with some new kids in town. She is worried about starting school again, but feels stronger with the support of her new friends and Joel. In an optimistic mood the diarist decides she no longer needs a diary; now she can communicate with her family and friends.
The epilogue states that the subject of the book died three weeks after the final entry. The diarist was found dead in her home by her parents, who came home from the movie theater. She died either by an accidental or premeditated drug overdose.
The diarist and her family reside in two different towns. The only description provided is that they are college towns.
The diarist describes running away to real locations in California and Oregon, and visiting New York City.