Jake Kimble, the sole survivor of the previous massacre, is confined to a psychiatric hospital in Chicago, haunted by the relentless ghosts of Kayako and Toshio. His skeptical caretaker, Dr. Sullivan, dismisses his terrifying stories of a vengeful, long-haired spirit, but she is forced to reconsider when Jake is brutally killed in his locked cell, his body broken by an invisible force.

Dr. Sullivan travels to the Chicago apartment building where Jake lived, the site where the curse first took root in the city. There, she encounters the Morrison family: the superintendent Max, his sister Lisa, and their ill sister Rose. Unaware of the danger, Lisa has entered the sealed crime scene of apartment 305, and the curse begins to claim new victims. As Max falls under the possession of the violent ghost Takeo, the family finds themselves caught in a spreading wave of rage and death.

Meanwhile, news of the escalating curse reaches Naoko Kawamata in Japan, the sister of the malevolent Kayako. Naoko travels to Chicago, believing she holds the key to finally stopping the evil spirit. She explains to a terrified Lisa that she needs the help of a living person—specifically Rose—to perform a ritual to banish her sister’s ghost for good. As Dr. Sullivan races to understand the supernatural force and Naoko attempts the dangerous rite, the remaining survivors must fight to avoid becoming the next permanent residents of the Grudge.