Seventeen-year-old Leo Cantrell knows when people will die. Eighteen-year-old Cassie Stewart is working on her first Hollywood film. Leo discovers that members of the cast and crew are targeted for murder, pitting him, Cassie, and their mutual friends against an unknown serial killer. Leo knows when, but not who or where. The only clue is a tattoo on the killer's wrist, a tattoo no one on the film crew appears to have on display.

Cassie's police officer dad and his detective girlfriend come aboard to thwart the murderer's plans, but how do they stop someone whose identity remains hidden? With their death date rapidly approaching, Leo encourages the intended victims to turn the tables on their would-be killer, but when the plan goes horribly awry, all bets are off.

They Know When The Killer Will Strike concludes the stories begun in I Know When You're Going To Die and The Horror Film Killer.