As an ambulance arrives for the body of Mary Lisbon, the final Lisbon suicide, a group of neighborhood boys recalls the events of the past thirteen months.

It is June in suburbia, school is out, and summer has begun. Cecilia Lisbon, who at thirteen is the youngest of five cherubic Lisbon sisters slits her wrists while taking a bath. Her life is saved, but the hospital psychiatrist recommends that she be given a social outlet outside of school. Mr. Lisbon and Mrs. Lisbon allow the girls to throw a chaperoned party, at which Cecilia seems oblivious to her sisters and to the neighborhood boys who come as guests. Just as the party's awkwardness begins to abate, Cecilia asks to be excused. Ascending to her bedroom, she jumps out the window onto the fence below, and dies instantly.

Since the local cemetery workers are on strike, Cecilia cannot be buried, but is given last rites and taken to the mortuary freezer. The shocked community tries to come to terms with her death, the first death in the boys' lifetime. The tragedy only makes the remaining Lisbon sisters more fascinating to the boys, who manage to obtain Cecilia's surprisingly mundane diary and read it aloud obsessively to each other, imagining themselves into the girls' lives. Yet they can neither find nor intuit a ready explanation for her death.

Unsure of how to console the reclusive Lisbons, the neighborhood women send flowers, while the men organize to remove the fence on which Cecilia landed. Neither act receives much response from the Lisbons, but the neighborhood feels its duty has been done. Summer ends, and the four remaining Lisbon girls return to school, where they keep largely to themselves. Mr. Lisbon, a high school math teacher, arrives early and throws himself into his work. Lux Lisbon, the prettiest of the sisters, has several clandestine relationships, despite her parents' categorical ban on dating.

Returning one afternoon from his usual smoke-up, Trip Fontaine, the local dream boy, ducks into the wrong classroom to avoid the headmaster. Seeing Lux, he falls irrevocably in love. At a school assembly, Trip invites himself to the Lisbon house to watch television, but finds upon arrival at the house that he has consigned himself to an evening at Mrs. Lisbon's side, able only to catch occasional glimpses of Lux's feet. As Trip sits in his car afterward lamenting the evening's failure, the car door opens, and Lux bursts in and begins voraciously kissing him. A moment later, she flees back into the house. Lux is grounded and Trip is hers.

As autumn progresses, the Lisbon house begins to physically deteriorate. The school holds a belated Day of Grieving, an oblique response to Cecilia's death, during which the hesitant teachers speak in general terms about sorrow while the Lisbon sisters spend the day in the bathroom. The school also hires a social worker, and although it is unknown whether the sisters actually confide in her, their spirits seem to lift and they begin to make friends. Trip Fontaine, via Mr. Lisbon, obtains Mrs. Lisbon's consent to take Lux to Homecoming on the conditions that Trip find dates for the other girls, that they all go in a group, and that the girls are home by 11 p.m.

On the night of Homecoming, the girls are radiant, despite their unnaturally coiffed hair and shapeless homemade dresses. The three neighborhood boys whom Trip has picked for Mary, Bonnie, and Therese are surprised to find the sisters engaging and completely normal. The sisters seem to enjoy themselves tremendously, and to no one's surprise Trip and Lux are voted Homecoming King and Queen. After the dance, Trip and Lux are nowhere to be found. The other boys take their dates home, but Lux does not arrive home until well after midnight, having been persuaded by Trip to sneak out of the dance and make love on the football field. After they make love, Trip abandons Lux, who is forced to walk home alone.

In response to Lux's disobedience, Mrs. Lisbon withdraws the girls from school, restricts them to the house, and draws the curtains of the house. She will later claim she wanted to give her daughters time alone to recover from Cecilia's suicide. Shortly afterwards, the boys begin to see Lux on the roof of the Lisbon house at night having sex with unknown men. When an ambulance appears at the Lisbon house several weeks later and Lux is wheeled out clutching her stomach, the neighborhood fears another suicide. In fact, Lux has faked a burst appendix in order to be taken to the hospital, where she can secretly obtain a pregnancy test. It is negative, and the sympathetic doctor tells her parents she had indigestion. Lux returns home.

The Lisbon house continues to deteriorate. In January, due to local parents' requests, a progressively unstable Mr. Lisbon is fired from his teaching post. In the months that follow, no one is seen leaving the Lisbon house, and even the grocer stops his weekly deliveries. In April, as spring breaks, the Parks Department comes to cut down the Lisbons' elm, which has caught Dutch elm disease. As the Parks Department is about to finish the job, the girls burst from the house and defiantly ring the dead stump, and the Park Department moves the tree indefinitely far down its lists of removals. Just as the boys begin to feel they have lost the girls entirely, notes begin appearing in the boys' bicycles and shrubbery. The boys, after several efforts, succeed in telephoning the Lisbon girls, playing a record over the phone, giving the girls their phone number, and hanging up. The next day the girls call back with a song, and the two groups trade songs all evening until the girls are forced to hang up. The boys' subsequent calls are not answered, but a note appears requesting their help on midnight of June 15th.

Arriving at the Lisbon house as instructed, ready to flee with the girls across the country, the boys find Lux smoking alone in the living room. She instructs them to wait in the living room for her sisters to finish packing while she, Lux, waits in the car. The boys wait until they are finally too suspicious. They begin to explore the house and find Bonnie's body hanging dead in the basement. Horrified, the boys flee home. Later, the boys realize that all the girls must have killed themselves—Bonnie by hanging, Therese by sleeping pills, Lux by asphyxiation—while the boys waited in the living room. Mary, who stuck her torso in the oven, is the only one whom the paramedics can save.

Though Mary will survive for a month more, the community assumes she is as good as dead. The Lisbons hire a housecleaner and put the house on the market. The media descends on the neighborhood, concocting sensationalist and factually incorrect stories about the girls' lives and deaths. In July, Mary finally dies by taking sleeping pills. Coincidentally, her death marks the last day of the cemetery workers' strike, so she and her sisters can all be buried properly. After the funeral, the Lisbon parents move away, and a new young couple buys their house and begin renovations.

At novel's end, the neighborhood boys, now middle-aged men, trace the suburb's decline following the Lisbon deaths, and lament the girls' suicides as selfish acts from which they have never been able to recover.

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