In the peaceful rural village of Hinamizawa, a dark secret festers beneath the surface of seemingly ordinary life. The annual Watanagashi Festival, meant to honor the local deity Oyashiro-sama, is overshadowed by a sinister pattern: for four consecutive years, a murder and a disappearance have occurred on the festival's night, events the villagers attribute to a curse. The story focuses on the close-knit group of friends who find themselves entangled in this mystery.

Keiichi Maebara is a charismatic newcomer who moves to Hinamizawa and quickly befriends his new classmates. Rena Ryugu is a kind-hearted girl with an obsession for collecting cute objects, but she hides a darker past and a fierce protective instinct. Mion Sonozaki is the tomboyish leader of the school club, next in line to head the powerful Sonozaki family, one of the village's three founding houses. Her identical twin sister, Shion, lives in the nearby town of Okinomiya and carries a deep resentment toward her family. Rika Furude is the young shrine maiden revered as the reincarnation of Oyashiro-sama, whose behavior hides a secret knowledge of the tragedies to come. Satoko Hojo is a cheerful prankster living with Rika after her parents were killed in a previous disaster. The police detective Kuraudo Oishi is an outsider obsessed with proving the curse is a cover for murder, while the photographer Jiro Tomitake and the nurse Miyo Takano are mysterious newcomers with a keen interest in the legend.

The live-action television adaptation presents its story through a series of arcs, each revisiting the same June 1983 timeframe from different perspectives. In the first arc, Keiichi learns from Oishi about the curse and becomes increasingly paranoid that his friends are planning to kill him. As he investigates, he discovers the dam construction conflict that motivated the first murder years ago, and his fear spirals into violence. The second arc follows Shion as she infiltrates the Sonozaki family to avenge a lost love, leading her down a path of torture and murder. The third arc sees Keiichi take drastic action to protect Satoko from her abusive uncle, only to find the body he buried mysteriously vanishes. The final arc shifts to Rena as the protagonist, who uncovers a conspiracy after a friend dies on the festival night and leaves behind cryptic notes about the curse, forcing her to confront traumatic memories from her past in Ibaraki.

The narrative structure is defined by its repetition with variation. Each arc begins with the same peaceful days of club games and friendship, only to descend into paranoia, madness, and murder. Clues scattered throughout each cycle gradually reveal that the curse is not supernatural but the result of a latent parasitic condition known as Hinamizawa Syndrome, which causes extreme paranoia and homicidal rage. A shadowy government organization, the Mountain Dogs, works to cover up the syndrome's existence, while the true mastermind behind the annual deaths is revealed to be Takano, who orchestrates the murders to fulfill her own obsession with proving her grandfather's medical research. Rika, trapped in a century-long time loop, has relived these tragedies countless times and works subtly to guide her friends toward the one future where they can all survive. The arcs build toward a final confrontation where the friends must unite, overcome their suspicion, and defy the fate that has claimed them in every other timeline.