Sometime after the events in Critters 2, Charlie MacFadden is tracking down the last of the Critters. A family of three – Annie (the main protagonist), Johnny (her little brother) and Clifford (the father) – stops at a rest stop when their car's tire pops. At the rest stop, Charlie warns them and Josh, stepson of a corrupt landlord, about the Critters. As this happens, a Critter lays eggs under the family's car and the family leaves, unknowingly taking the eggs with them. Soon after they arrive at their tenement, the Critters hatch and attack the sleazy maintenance man, Frank. When the landlord arrives, he too is eaten by the Critters after Josh locks him in Clifford's room, unknowingly trapping his stepfather with the creatures. Next, one of the residents is attacked and wounded. Annie, her family and five others (including Josh) try to get to safety in one piece by getting to the roof of the building. Charlie arrives and destroys the remaining Critters, saving the remaining tenants. The film ends in a cliffhanger as Charlie is about to destroy two Critter eggs, but is ordered not to and a containment pod sent from the Intergalactic Council crashes into the basement.
Although unexplained, it is revealed that one stray Crite has survived the second film's events and Charlie is encountered by Annie, Josh and Johnny at the film's beginning, hunting the last one down. He explains the events that happened in the first two films to them, and warns them that he only has one left. He also gives Johnny a crystal that glows green when it detects Crites nearby, before leaving to search.
Charlie is not seen again until the Crites have attacked the tenement building that Annie lives in. Mr. Menges had called him to ask him questions about the Crites when Johnny's crystal starts glowing green, and Charlie had made it to the building, just in time to save Annie from several Crites. He reunites with the survivors, and shoots a Crite that attacks them, leaving an entry to the roof. On the roof, Charlie dives in front of Johnny to save him from a Crite attack, and ends up hanging onto a pole dangling off the building. It doesn't last long and Charlie collides with Cliff's van, eventually discovering the dead Crite speared on an aerial.
Charlie bids farewell to the survivors and searches the building's burnt basement level, in search of stray Crites. He finds only two eggs remaining, and then suddenly, his Communicator rings out loudly, warning him that he is in violation. A hologram of Ug appears and explains that under Intergalactic law, he cannot destroy the last two eggs as that would render the Crites extinct. Ug tells Charlie a specimen collection pod has been dispatched to send the eggs back to the Council, and that he is tasked with putting them in there. The film ends just as the pod bursts through the roof.