Five years after the events of Sadako 3D, the world believes the curse of the deadly video has ended. Akane Ayukawa gave birth to a daughter, Nagi, but died soon after due to complications from the birth. The child's father, Takanori Ando, is overcome with guilt and blames Nagi for Akane's death, leading him to abandon the girl to be raised by his younger sister, Fuko Ando. Fuko, a graduate student of psychology, cares for her young niece while Takanori works as a security guard at Asakawa General Hospital, keeping his distance from the family.

Fuko grows increasingly concerned as strange events begin to unfold around Nagi. The young girl is quiet and isolated, preferring to draw disturbing pictures that have a habit of coming true. When a bully from Nagi's kindergarten is found drowned in a river, Fuko realizes Nagi had drawn the scene beforehand. More deaths follow, from the family babysitter to a packed train car full of passengers, all seemingly predicted by Nagi's artwork. Fuko consults with her psychiatrist professor, Dr. Fumika Kamimura, who initially dismisses Fuko's fears as a projection of her own traumatic childhood, during which she witnessed her mother's suicide.

Meanwhile, Detective Mitsugi Kakiuchi is assigned to investigate the bizarre string of suicides. His own wife was the first victim, who stabbed her own eye after viewing something on her laptop. Kakiuchi seeks out Detective Yugo Koiso, who was disabled during the events of the first film, and learns the truth about Sadako Yamamura and her failed attempt to possess Akane. Shortly after their conversation, an unseen force pushes Koiso's wheelchair down a flight of stairs, killing him.

Determined to get answers, Fuko visits the imprisoned Seiji Kashiwada, a serial killer awaiting execution who helped facilitate Sadako's rebirth in the previous film. Kashiwada chillingly reveals that Nagi is not Akane's biological daughter, but the child of Sadako. He tells Fuko that the only way to stop the curse is for her to kill either herself or the little girl. Fleeing in terror, Fuko is lured into a trap by Dr. Kamimura, who has been possessed by Sadako's influence. Fuko manages to escape, but not before being forced to watch the cursed video, marking her for death.

Fuko confronts Takanori, demanding the truth. He takes her to a hidden room in the hospital where Akane lies in a comatose state, kept alive to contain Sadako. Takanori explains that Akane allowed herself to be possessed by Sadako to fight her from within, but this struggle resulted in a supernatural pregnancy. Nagi was born, but Akane cannot wake up or touch her daughter, as any contact would allow Sadako to fully escape into the world. Takanori insists Nagi is innocent and not responsible for the deaths, which are actually caused by Sadako's lingering influence reaching out from Akane's body.

The situation spirals out of control when Detective Kakiuchi, driven mad by his wife's death and his own exposure to the curse, tracks Nagi to the hospital. He brutally attacks Takanori and shoots the comatose Akane before turning the gun on himself. As Akane dies, the room floods with blood pouring from a phantom well. Sadako emerges to claim Nagi as her daughter. In the final confrontation, Fuko refuses to give up on the child. She manages to pull Nagi back from Sadako's grasp, proving that Nagi has a human family who loves her and will not surrender her to the ghost.

Days later, Fuko and Nagi share a peaceful picnic in a meadow, having formed a new family together. However, a final scene reveals that the detective had been watching a security recording, which shows that while Nagi was a candidate, the true biological child of Sadako is actually someone else entirely, leaving the threat of the curse still lurking in the shadows.