Chance and Jake see the movie “Hard Shell”, about a giant alien beetle, at the Megakat Multiplex. Chance, who hates bugs (or rather, is afraid of them), is upset because he thought “Hard Shell” was about a tank. As they leave the theater, Chance spots what he thinks is a shooting star, but Jake tells him it’s the M.A.S.A. probe KatSat 1 returning from orbit. The probe lands in the desert, where astronomer Dr. Harley Street, accompanied by Ann Gora, arrives to retrieve it. Dr. Street tells Ann he can’t answer any of her questions yet until he has examined the probe back at his lab, but invites her to stop by the space center tomorrow for an interview. No one notices the yellow goo that is oozing from the side of the probe.
Later that night, back at the M.A.S.A. center, Dr. Street is examining the probe, and he notices the goo. As he pokes at it, a half kat, half bug creature (dubbed a “Ci-Kat-A” in the title) emerges and bites his finger, causing his eyes to turn bug-like and his mind to be under its control. Dr. Street than takes the Ci-Kat-A around the building, allowing it to bite and infect all the staff and guards. The next day, as he is working on a car, Chance is startled by a spider, and as he flails around trying to get it off, he accidentally hits Jake with a wrench. Annoyed, Jake asks Chance if he’s “a kat or a mouse”.
Ann Gora and her camerakat Jonny arrive at the M.A.S.A. space center, but the possessed Dr. Street (wearing sunglasses to hide his bug eyes), rudely tells them to go away. Ann is suspicious, refusing to leave without a story, and she and Jonny begin to look around, and find the room in which the center’s nuclear reactor is held, which is now filled with Ci-Kat-A cocoons. They are chased away by a bug-eyed guard, and run into the queen Ci-Kat-A (now as big as a normal-sized kat), which attacks them. Jonny’s camera is broadcasting everything live, and when Chance and Jake see the Ci-Kat-A on their TV, they think it’s a monster movie until they see the terrified Ann. Meanwhile, the Ci-Kat-A begin to hatch from their cocoons, and to escape, Ann and Jonny hide in the cockpit of a space shuttle.
The SWAT Kats arrive, and so do the Enforcers. While Feral and his men take heavy fire from the center’s defensive cannons (operated by the bug-eyed staff), the Turbokat lands and T-Bone and Razor take the back entrance. They spy on Dr. Street and the queen Ci-Kat-A, who is complaining that the food (energy from the nuclear reactor) has run out, and are attacked by the bug-eyed guards. They defeat them easily, but then in come the smaller Ci-Kat-As. The SWAT Kats join Ann and Jonny in the shuttle (one Ci-Kat-A even gets locked in with them), and Dr. Street launches the craft in an effort to get rid of them. However, the SWAT Kats bail out of the shuttle (with Ann and Jonny clinging to them) and parachute to safety. Meanwhile, the Ci-Kat-A invade two of the Enforcer choppers, infecting the pilots, who turn on Feral and fire at him.
Mayor Manx calls him and asks how the “bug problem” is. Feral, chasing after the two infested choppers with his one remaining wingman, assures Manx that all is well. At City Hall, Manx tells Callie to run out to M.A.S.A. to check on things, since Megakat Towers is reopening, and he doesn’t want any trouble. After a safe landing, the SWAT Kats see Dr. Street drive off in a van, with the queen Ci-Kat-A, and chase after them in the Turbokat. Razor theorizes they’re going to the Megakat Nuclear Plant. Not far away, Feral runs into trouble as his wingman’s chopper is overtaken by a Ci-Kat-A and he finds himself against three enemy aircraft. The SWAT Kats see his plight, and shoot down two of the choppers, leaving him with only one to face. Razor turns out to be correct, as they see Dr. Street’s van headed for the Nuclear Plant, and Razor takes the Cyclotron and chases after it.
After a harrowing chase, both the van and the Cyclotron are wrecked, and the queen Ci-Kat-A cocoons Razor. They go inside to the reactor room, and the queen Ci-Kat-A feeds off of the nuclear reactor core, growing bigger. Meanwhile, Feral is still having trouble with the final Ci-Kat-A chopper, until T-Bone arrives and shoots it down, too. They then head over to the Nuclear Plant. T-Bone lands and frees Razor from the cocoon, and the queen Ci-Kat-A bursts from the building and takes flight, carrying Dr. Street (who is now starting to turn into a bug himself) with her.
Feral gives chase, but the Ci-Kat-A knocks his chopper down. He calls for backup, with lots of bug spray. The SWAT Kats hop into the Turbokat and give chase to the Ci-Kat-A queen, but she gums up the jet’s intakes with he cocoon-ish spit, nearly making them crash. When they finally regain control of the Turbokat, they notice the Ci-Kat-A has gone. So, they head back to the hangar to clean out the intakes.
Later, Callie arrives at the newly rebuilt Megakat Towers and goes up to the penthouse, only to find it full of Ci-Kat-A eggs. She is suddenly attacked by Dr. Street, who has now fully mutated into a winged, mandible insect-kat. She manages to call the SWAT Kats, who arrive just in time to stop Dr. Street from biting her. They shoot him in the face with an Octopus Missile, sending him flying through a window, and he plummets to his death. Feral and his choppers arrive, and destroy the eggs with flame-throwers.
This incredibly upsets the queen Ci-Kat-A, who once again causes Feral’s chopper to crash after the bugspray fails. The SWAT Kats fly in, and tie up the queen’s wings with a grappling hook and some cables, but as she falls, she grabs Razor from the cockpit, taking him with her as she plummets. Luckily, he frees himself from her grasp and uses his Gloavtrix’s grappling hook to swing to safety. Down below, Mayor Manx arrives in his limo with Mr. Young to show him the building, when the queen Ci-Kat-A lands in front of the limo.
She threatens them, but then a huge chunk of the burning wreckage from the penthouse above falls and crushes her, splattering bug guts all over Manx, Young, and their driver. Sorrowfully, Manx tells the driver to go back to the airport. Back at home, Chance and Jake see an ad on TV for “Hard Shell 2: The Revenge”, and Chance asks Jake if he wants to go see it. Jake declines, saying he’s had enough big bug action, and Chance says handling the big ones makes the small ones tame by comparison – until the one he’s holding bites him.