Ten years have passed since the Haddonfield massacre, and the silent killer Michael Myers has been in a comatose state, locked away in a maximum-security facility. On the eve of Halloween, Myers is being transferred to a different institution. During the transfer, he awakens upon overhearing that he has a surviving niece, Jamie Lloyd, living in his hometown of Haddonfield. Driven by a mysterious and unyielding force, Myers escapes the transport, claiming more victims in his wake and setting his murderous sights on returning to Haddonfield to find his young niece.

In Haddonfield, young Jamie is trying to lead a normal life, but she is haunted by nightmares of her murderous uncle. Living with her foster family, the Carruthers, Jamie struggles with the weight of her familial legacy. Her foster sister, Rachel, tries to provide support and comfort. As Halloween night approaches, the town's residents remain blissfully unaware of the looming threat. Dr. Sam Loomis, the obsessed and determined psychiatrist who once treated Myers, learns of the escape and rushes to Haddonfield in a desperate bid to protect Jamie and stop Myers before he can resume his killing spree. The town becomes a backdrop for a terrifying cat and mouse game as Myers draws ever closer to his intended target.