As the film begins. A former criminal and drug dealer Lucky (Wesley Snipes) was released from prison and tries to lead a respectable life despite his troubled past. However, Lucky once or twice reflects on the wisdom of his grandfather who supposedly told him "sometimes without bad luck, it would seem you don't have any luck at all." Shortly after his release from prison, Lucky tries to get back on his feet but inexplicably ends up a victim of Hurricane Katrina's wrath, and loses his newly found life. After Lucky returns to New York, Lucky is dealt another blow when the government withdraws funds for his yoga and samba dance classes which he uses to try to keep kids off the streets. This unfortunate event leads to Lucky enduring the bad influences of two old friends from his past life as a criminal, who lure Lucky to a strip club under the false pretense of his friend's birthday. When a drug deal with some dangerous mobsters goes bad, and Lucky is now on the run with a feisty Puerto Rican stripper from the strip club, Angela (Jacquelyn Quinones), and over $500,000 in American currency, which is wired with marking dye. Later that night, there are short cuts of an unconventional and troubled couple, unexplained and also known to the police as the "Sawtooth Killers". Chang (James Liao), an egotistical and maniacal accomplice to his old-fashioned girlfriend Cass (Cybill Shepherd), the mother of a mentally challenged man named Eugene (Mike Messier). Motivated by Cass's son Eugene is unpleasant experiences with society's rejection of mentally challenged individuals, the couple brutally kidnaps, tortures, and presumably kills their abductees, recording their exploits on video, possibly for future viewing. Angela and Lucky find themselves caught up in the path of violence, and Lucky ends up an unlikely hero by saving the life of a would be victim of the Sawtooth Killers. However, Lucky saving Captain Davis (Mario Van Peebles), from Cass's son Eugene who is armed with a shovel. Lucky choosing to have a positive outlook on the events by using perspective gained from his grandfather, characterizes the events as being "the luckiest day in an unlucky man's life." Lucky and Angela go on to receive a $200,000 reward which had been offered by the police for information leading the capture, arrest, and or prosecution of the Sawtooth Killers.

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.