Fourty years ago, Harriet disappeared from a family gathering on the island owned and inhabited by her powerful family. Her body was never found. Her uncle is convinced it was murder and that the killer is a member of his own tightly knit but dysfunctional family. He employs a disgraced financial journalist and a tattooed, ruthless computer hacker to investigate. When the pair link Harriet's disappearance to a number of grotesque murders from almost forty years ago, they begin to unravel a dark and appalling family history. But the family are a secretive clan and are about to show just how far they are prepared to go to protect themselves.

Taking place almost exactly after Critters 3, Charlie McFadden places the last two remaining Crite eggs inside the preservation capsule as instructed by Ug. Charlie is somehow also locked inside and sent into space, where he remains in hibernation until a salvage ship finds the pod in the year 2045. The crew (which includes Captain Rick, Fran, Bernie, Al Bert, and young Ethan) reluctantly report the discovery to the Terracorp Council, upon discovering their old logo on the side of the pod. They then go to an abandoned Terracorp station to await the arrival of the council. The station is actually on its last legs and will blow up within a month or so. Furthermore, the station is controlled by a computer called Angela, which only takes orders if given the opposite instruction: working on the flawed logic that the crew are not authorised to have access and it should do the opposite of what they command. A selfish Rick however decides to open the pod early, freeing Charlie but also letting loose two young Crites which kill Rick and escape, while the crew constantly bicker about where to go from there. After a close call in a waste disposal unit, Charlie and Ethan are rescued by Bernie. Charlie learns from the others that he is no longer in 1992, and that everybody he knew on earth is now dead. Ethan finds a lab coat containing a keycard. But just like Rick earlier, Bernie strays from the group, takes the keycard with him and is then killed by the now adult Critters inside a pharmacy room. Following an attack from a lone Crite, Charlie carelessly uses an antique gun to kill it, but ends up deactivating the ship with only one bullet remaining. From then on, the crew are sitting ducks. Ethan then dashes off to search for the remaining Crite, shouting at Al Bert. Terracorp arrives shortly thereafter, but they are not there to negotiate payment. They simply want the Crite eggs returned to them. Ug, now a corrupt businessman going by the name Counselor Tetra, kills an uncooperative Al Bert, and threatens to kill Fran next unless the eggs are returned. Charlie is upset, barely accepting that his old friend has now become a traitorous villain. Tetra sends his guards to find the Crites, but the nuclear reactor begins a 10 minute self-destruction sequence. Ethan lures the guards into a room full of genetically altered Critters, which kill the guards. After killing the lead Crite, Ethan is threatened by Tetra at gunpoint. Charlie re-appears and shoots his former friend without any hesitation. With the Critters now extinct, Charlie, Ethan and Fran take Ug/Tetra's ship and begin their delayed flight back to Earth.