On the morning an ambulance arrives for the body of Mary Lisbon, the final Lisbon suicide, a group of neighborhood boys recalls the events of the past year leading up to Mary's death.
The Lisbons are a Catholic family living on the elm lined streets of a decaying suburb in Grosse Pointe Michigan during the 1970s. The father, Ronald, is a math teacher at a private school, and the mother is a homemaker. The family has five enchanting daughters: 13-year-old Cecilia, 14-year-old Lux, 15-year-old Bonnie, 16-year-old Mary, and 17-year-old Therese.
Their lives change dramatically within one summer when Cecilia, a stoic and astute girl described as a "cherubic misfit", attempts suicide by slitting her wrists in a bathtub. She is found in time to be saved and survives the attempt. A few weeks later, the Lisbon parents allow the girls to throw a chaperoned basement party in hopes of cheering Cecilia up. However, after the neighborhood boys arrive as guest, Cecilia excuses herself and ascends upstairs to her bedroom. Seconds later the party hears a moist thud. In the sudden deadness of silence and anticipation, filling the gap between event and realization, everyone knows Cecilia has jumped out her window, instantly dying when she is impaled by one of the iron spikes of the fence post below.
Cecilia's suicide and its aftermath force the Lisbon parents to begin to watch over their four remaining daughters even more closely. This further isolates the family from the community and the gossipy neighbors and heightens the air of mystery and intrigue about the Lisbon sisters to the neighborhood boys in particular, who long for more insight into the girls' unfathomable lives.
When school begins in the fall, the girls return as if nothing has happened. Lux, the most rebellious of her sisters and described as a "carnal angel", begins a secret romance with local heartthrob Trip Fontaine. Determined to be with Lux, Trip negotiates with the overprotective Mr. and Mrs. Lisbon to take Lux to a homecoming dance, on the condition that he finds dates for the other three girls, to go as a group. After winning homecoming king and queen, Trip persuades Lux to ditch the dance to have sex on the high school football field. Afterwards, Trip becomes disenchanted with Lux and abandons her. As a result, she misses her curfew. In response to Lux's disobedience, Mrs. Lisbon withdraws the girls from school, draws all the curtains of the house and restricts them in "maximum security isolation". She will later claim she wanted to give her daughters time alone to recover from Cecilia's suicide, rather than just punishing them.
Soon, the Lisbons sink into a reclusive lifestyle and rarely leave their home, with the exception of Mr. Lisbon, who drives to and from work, and the family attending church on Sunday. Despite Mrs. Lisbon's attempt to protect her daughters from the outside world of boys and sex, over the winter a promiscuous Lux is seen at night having sex on the roof of the Lisbon residence with unknown men. The neighborhood boys spy and secretly watch Lux in action from across the street. A few months after, Lux is sent to the hospital because of a pregnancy scare, which her parents are told was simply indigestion. Not much later, an unstable Mr. Lisbon officially takes a leave of absence from his teaching job. Their house falls into a deeper state of disrepair; none of them leave the house and no one visits, not even to deliver milk and groceries. The neighborhood smells a foul stench coming from the Lisbon house, that permeates the entire block. From a safe distance, the community watches the Lisbons' lives slowly deteriorate, but no one can summon up the courage to intervene. After months of confinement, the sisters reach out to the boys across the street by using light signals and sending anonymous notes. The boys decide to call the Lisbon girls and communicate by playing records over the telephone for the girls to share and express their unrequited feelings.
Finally, the girls mysteriously send a message to the boys to come over at midnight, leading the boys to believe they will help the girls escape and elope with them. When they anxiously arrive, they meet Lux who is alone and smoking a cigarette. She invites them inside and tells them to wait for her sisters while she goes to start the car. As the boys wait, they briefly fantasize about the Lisbon sisters, not realizing that meanwhile, the girls are killing themselves in the surrounding darkness. Curious, they begin to explore the house and wander into the basement. Here, they discover a freshly dead Bonnie hanging from a rope tied to the ceiling rafters. Disillusioned and horrified, the boys immediately flee back to their own homes.
In the morning, the authorities come for the dead bodies, as the girls had apparently made a suicide pact: Bonnie hanged herself, Therese overdosed on sleeping pills, and Lux died of carbon monoxide poisoning after sealing herself in the garage with the family's station wagon running. Mary attempts suicide by putting her head in the gas oven, but later it is revealed that her attempt fails. She is the only one whom the paramedics can save.
Mary continues to live for another month, but the community assumes she is as good as dead. Eventually, Mary successfully ends her life by taking an overdose of sleeping pills like Therese on the same day of another neighborhood girls' debutante party. Coincidentally, her death also marks the last day of the local cemetery workers' strike, so she and her sisters can all be properly buried together. Seemingly unsure how to react, the adults in the community go about their lives as if nothing has happened. Local newspaper writer Linda Perl notes that the suicides come exactly one year after Cecilia's first attempt, and incorrectly describes the girls as tragic creatures so cut off from life, that death wasn't much of a change.
After the "suicide-free-for-all" and the funerals that followed after it, Mr. and Mrs. Lisbon quietly leave the suburbs, never to return. Thus, giving up on any attempt at living normal lives. The Lisbon house is cleaned out and any evidence of the girls' existence is erased. Once the house is emptied, it's quickly sold to a young couple from the Boston area. All the furniture, items and personal belongings of the Lisbons are either thrown out or sold in a garage sale. The narrators scavenge through the trash to collect much of the "evidence" to save as keepsakes and mementos they will treasure forever.
The boys never forget about the Lisbon sisters, however much they try. The five dead girls and their baffling fates forever haunt them and remain a source of mystery and lost innocence they reflect upon throughout their lives. The boys, now middle-aged men with wives and families of their own, lament the suicides as selfish acts from which they have never been able to emotionally recover. The novel closes with the men confessing that they had loved the girls, who hadn't heard them calling. And despite their life-long efforts, will never know the true motives behind the Lisbon sisters' actions to understand why they chose to be alone in suicide for all time.