Thirteen-year-old Cecilia Lisbon slits her wrists in the bathtub, and the paramedics take her to the hospital where she's cared for and discharged a week later. At the suggestion of her psychiatrist, her parents let their five daughters throw a party, which the narrators, a chorus of neighborhood boys, attend. During the party Cecilia goes upstairs and throws herself out of a window onto an iron fence spike, this time succeeding in killing herself, gruesomely and very publicly.
The adults attend Cecilia's funeral, and the boys become obsessed with explaining why she did it. They get hold of her diary and try to recreate her final hours, and become obsessed with her surviving older sisters, whose lives seem to be controlled by their religious and repressive mother. The girls keep to themselves, so the narrators don't know much about them except what they can deduce from spying on them. The neighborhood dads pull down the fence that impaled Cecilia.
Fourteen-year-old Lux Lisbon attracts the attention of Trip Fontaine, the hottest guy at school, but overall the family keeps a low profile after Cecilia's death, almost never leaving the house. The school holds a "Day of Grieving" for Cecilia, but no one really knows how to act so it's kind of a joke. They don't even mention Cecilia or suicide. Trip asks the girls' dad, a teacher at school, if he can take Lux to homecoming. The Lisbons agree to let the girls go out on a group date with Trip and three of his friends. The boys find the girls to be surprisingly normal once they're out of the house.
Mary Lisbon dances while Lux and Trip hide under the bleachers to make out. At 10:30 it's time to go home, but Lux and Trip, homecoming king and queen, are nowhere to be found. The other four girls go home without her. Trip takes Lux to the football field, where they have sex; he sends her home alone, disgusted with her. After that night the girls are pretty much under house arrest by their parents, not even allowed to go to school.
Lux starts receiving randos on the roof for sex. One day she fakes a burst appendix so she can get to the hospital for a pregnancy test (it's negative, but she has HPV). At Christmastime Mr. Lisbon loses his job at the high school and the family really goes downhill. The house falls into disrepair and the neighbors get only occasional glimpses of the family, who seem to be falling into disrepair themselves.
The girls start leaving mysterious messages and Virgin Mary cards around the neighborhood, and the boys decide to call them on the phone. The girls suggest that the boys meet them on the night on June 16, presumably to plan their escape. The boys agree to go save the girls, offering to drive them to Florida. Lux greets them on the designated night and tells them she'll wait in the garage while her sisters finish packing. Actually, the other sisters are in the process of dying: Bonnie hangs herself in the basement, Mary puts her head in the gas oven, Therese takes a lethal dose of sleeping pills and Lux leaves the car running in the garage and dies from the carbon monoxide. It's exactly one year after Cecilia's first suicide attempt.
The paramedics come and are only able to save Mary. She lives for another month with her shell-shocked parents in their empty house. The rest of the neighborhood tries to forget the tragedy, distracting themselves with a party. That night Mary finally makes her escape, overdosing on sleeping pills. The narrators, looking back on that horrible year 20 years later, realize they'll never understand what happened.