Picking up exactly where Critters 3 left off, Bounty Hunter, Charlie McFadden, is about to fire his gun on the last two Critter-eggs when he gets a message that it would be illegal to extinguish the race from the galaxy. A transporter is sent to him, where he puts the eggs. However, the transporter also takes him with it where he then gets lost in space. After 53 deep-frozen years, he's found by a private wreckage collector team, captained by the unscrupulous Rick. On behalf of the mighty company Terracor they bring him to an empty space station - but Rick is curious and opens Pandora's box... so Charlie has work again, to keep the Critters from eating everybody.
Charlie puts the Crite eggs into coffee cans and gets into the pod, placing them into their receptacles. The door closes on him, and he is unable to escape the pod before it puts Charlie and the Crite eggs into a deep hypersleep.
53 years later, the pod is encountered by the R.S.S Tesla, a salvage craft, who capture the pod and are contacted by Ug (now a businessman named Counselor Tetra). The crew travel to the nearest TeraCor space station, and the greedy captain, Rick, decides to breach the pod despite Tetra's instructions. He manages to open the pod's door, while Charlie wakes up and in a panic, exits the pod, bumping into Rick. Deciding to investigate, Rick enters the pod and discovers the coffee cans, now containing broken Crite eggs. The two baby Crites attack Rick, with one viciously jumping into his mouth and eating his tongue and gums. Charlie tries to shoot them but his gun falls apart, so as the Crites finish off Rick, Charlie grabs Rick's laser gun and fires, only singeing the head of one of them. The Crites roll away, and Charlie befriends a comatose Ethan, who had been knocked out by Rick earlier.
The pair make their way through an abandoned lab and accidentally fall into the ship's garbage refuse system. After narrowly escaping decompression, Charlie tries to explain his story to Ethan, Fran, Bernie and Al Bert, but they are dismissive of it, since Charlie still believes he is in the year 1992. He faints after hearing what year it actually is.
He wakes up while the crew watch a film about TeraCor's intentions with intergalactic lifeforms, then he becomes nervous when the crew discover Bernie has wandered off alone to the station's pharmacy to steal drugs. He implores Al Bert to call Bernie back when two lifeforms show up on the map scanner, insisting that "It's them!". Bernie however ignores their warnings and is attacked by the Crites and killed. As the crew attempt to leave the space station, they encounter a nest of Crite eggs, so Charlie explains that they take six months to incubate, when an angry Fran tries to crush them.
When they get to the Tesla, a Crite attacks through a vent and Charlie haphazardly shoots at it, and kills it but also destroys the ship's electronics, grounding them at the space station (while the nuclear core begins to melt down). Charlie helps with the repairs, but a TeraCor ship arrives with Ug on it. Charlie is shocked when Ug has seemingly turned traitor and now only cares for retrieving the eggs. He's even further shocked when Ug kills Al Bert with a gun, leaving only him and Fran. Ethan arrives to save them, having disposed of Ug's guards by luring them into a Crite-infested lab. He has the last remaining eggs, and juggles them, throwing them at the walls to antagonise Ug. Ug is eventually shot by Charlie himself, and the three escape in TeraCor's ship while the station is vaporised.
As Ethan and Fran explore the ship, Charlie dons sunglasses and fancies himself a ship captain, and presses a button on the control, which causes the ship to spiral out of control, ending the film.