The story takes place in affluent Grosse Pointe, Michigan, in 1974, as four neighborhood boys reflect on their neighbors, the five Lisbon sisters. Strictly unattainable due to their overprotective, authoritarian parents, Ronald (James Woods) and Sara (Kathleen Turner), the girls: 17-year-old Therese (Leslie Hayman), 16-year-old Mary (A.J. Cook), 15-year-old Bonnie (Chelse Swain), 14-year-old Lux (Kirsten Dunst), and 13-year-old Cecilia (Hanna R. Hall), are the enigma that fill the boys' conversations and dreams.
The film begins with the suicide attempt of the youngest sister, Cecilia, as she slits her wrist in a bath. The family therapist Dr. Horniker (Danny DeVito) suggests to Ronald and Sara and Cecilia may have a problem with feeling neglected and says that they should pay more attention to Cecilia and the rest of their children.
A few days later, Ronald and Sara throw a chaperoned party at their house which is intended to make Cecilia feel better. Cecilia excuses herself and jumps out her second-floor bedroom window, dying when she impales herself on an iron fence. In the wake of her act, the Lisbon parents begin to watch over their daughters even more closely, further isolating the family from the community and heightening the air of mystery about the Lisbon family and what they are really about.
At the beginning of the new school year in the fall, Lux forms a secret relationship with Trip Fontaine (Josh Hartnett), the school heartthrob. Trip comes over one night to the Lisbon residence to watch television and persuades Mr. Lisbon to allow him to take Lux to the Homecoming Dance by promising to provide dates for the other sisters, to go as a group. Mr. Lisbon agrees as well as volunteers to be one of the chaperones. After being crowned Homecoming Queen and King, Lux and Trip have sex on the football field. Lux falls asleep, and Trip abandons her immediately. Lux wakes up alone and has to take a taxi home.
Having broken curfew, Lux and her sisters are punished by a furious Mrs. Lisbon by being taken out of school and sequestered in their house. Unable to leave the house, the sisters contact the boys across the street by using light signals and sharing songs over the phone as a means of sharing their feelings.
During this time, Lux begins to have anonymous sexual encounters on the roof of the house late at night; the boys watch from across the street. Finally, after months of confinement, the sisters leave a note for the boys, presumably asking for help to escape. When the boys arrive that night, they find Lux alone in the living room, smoking a cigarette. She invites them to wait for her sisters, while she goes to wait in the car. The boys briefly imagine the group of them driving blissfully away on a sun-soaked country road.
The boys wander into the basement and discover Bonnie's body hanging from the ceiling. Terrified, they rush upstairs only to stumble across the bodies of the remaining sisters. They had all killed themselves in an apparent suicide pact moments before: Therese took an overdose of sleeping pills; Mary stuck her head in the gas oven; and Lux left the car engine running in the sealed garage.
Devastated by the suicides of all their children, Mr. and Mrs. Lisbon quietly flee the neighborhood in the middle of the night, never to return. Mr. Lisbon calls a friend to sell off the family belongings, especially those belonging to the girls, in a yard sale; whatever didn't sell was put in the trash, including the family photos, which the neighborhood boys kept as mementos of the mysterious girls. Soon after, a young couple from Boston purchases the Lisbon's house. Seemingly unsure how to react, the adults in the community go about their lives as if nothing important happened. Mr. and Mrs. Lisbon were never seen or heard of again. People in the community to this day talk as if the Lisbon family never existed. The five dead girls forever remain a source of mystery and grief for the boys, who cannot forget them. The film ends with one of the boys acknowledging in voice-over that they will spend the rest of their lives trying to put together the unsolvable mystery of the Lisbon sisters and why they choose to commit suicide.