The film opens with the police investigating the murder of high school girl Tomie Kawakami (Miho Kanno). They learn that in the months following the crime, nine students and one teacher have either committed suicide or gone insane. The detective assigned to the case learns that three years prior another Tomie Kawakami was murdered in rural Gifu prefecture. Other slain Tomie Kawakami's are discovered stretching all the way back to the 1860s, right when Japan began to modernize. The detective tracks down one of Tomie's classmates called Tsukiko (Mami Nakamura), an art student who is being treated for amnesia. She has absolutely no memory of the three-month period around Tomie's death, and is starting to suspect the cause has a supernatural source. Meanwhile, Tsukiko's neighbor is rearing a peculiar baby-like creature. Over the span of a couple weeks, it grows into a beautiful teenaged girl with orange eyes responding to the name of Tomie Kawakami.
Soon afterwards, Tomie begins seducing Tsukiko's boyfriend Yuuichi (Kouta Kusano). Meanwhile, Tskuiko enters her new neighbor's apartment to investigate. Upon discovering her friend's dead body, she is attacked by her landlord and passes out due to asphyxiation. She wakes up in her psychiatrist's office and encounters Tomie. Tomie starts emotionally taunting Tsukiko and tries feeding her live cockroaches. She then begins taking selfies next to her. Soon thereafter, Tsukiko's boyfriend murders Tomie. As they go bury Tomie's headless body in the woods, she comes back to life and Tsukiko runs off further into the woods and finds herself on a boat dock. Tomie then appears once again, now fully regenerated, and kisses Tsukiko on the lips. They both begin laughing as Tsukiko lights a flare and sets Tomie on fire.
Tsukiko is now shown leading a normal life, still taking photographs and being interested in art. One day as she goes to develop a picture she took of herself, she notices a mole under her left eye she didn't have before; the same kind of mole Tomie had. Tsukiko then looks at herself in the mirror in shock as Tomie appears, smiling.