The Turtles and the Shredder battle once again, this time for the last canister of the ooze that created the Turtles, with which Shredder wants to unleash an army of new mutants.
The turtles find out where the Ooze, the substance which made them mutate, came from. Unfortunately Shredder learns about it too, and uses it to enhance himself. So the turtles have to prove again who's the better ninja fighter.
- After their rooftop battle with the Foot Clan, the Turtles find themselves between homes and are living off pizza delivery from "Roy's" Pizza while staying in April O'Neil's new apartment with Master Splinter. When April covers the cleanup process underway in the city by TGRI, Splinter recognizes the initials from the canister of mutagen that turned them all into mutants. Meanwhile, the Shredder is alive and well, has resumed command of the Foot, and seeks revenge upon Splinter and his students. Upon learning of the potential for the ooze to mutate animals into minions, he sets out to obtain samples and scientists, kidnapping Professor David Perry of TGRI and forcing him to assist in the creation of two aressive mutants to be his own pupils: Tokka (a snapping turtle) and Rahzar (a wolf).
When the Turtles are discovered in April's apartment by Keno, the pizza delivery boy, they reveal their history and Keno tells them about the reborn Foot Clan's efforts to recruit people with fighting ability. Seeing the potential to infiltrate the Foot, Keno offers to sign up but Splinter refuses to put him in danger and believes that they ought to get out of April's apartment instead. Not willing to simply let the Foot Clan regroup, Rafael abandons the others during their search to team up with Keno while his brothers stumble upon an abandoned Subway Station under the city.
Professor Perry manages to contaminate the mutagen to ensure that Tokka and Rahzar will not grow intelligent as a result of the mutation in addition to growing. Shredder is persuaded not to kill them by the professor due to their incredible strength (which is greater than anything exhibited by Splinter's pupils). Ironically, they imprint upon the Shredder as their mother.
After infiltrating the Foot, Raphael discovers that the Shredder is alive only to be caught and used as bait. Keno gets word to the others and they try to save him from the Foot's base in the junkyard. There they are caught in a well laid trap. Master Splinter saves them and they fight the Foot and Shredder's mutants in an effort to escape with Professor Perry. They make it back to the home in the old Subway where Perry reveals everything he knows to his new friends.
Donatello and Perry begin workin on an anti-mutagen when April sends word that the Shredder intends to let them loose on a rampage in Central Park if the Turtles fail to show at a fight to the death at a local construction sight. The Turtles, armed with anti-mutagen doughnuts, face Toka and Razar and the fight spreads to a local nightclub where they interupt a performance by Vanilla Ice and Ninja Rap is born. The doughnuts do the trick and the Turtles again confront the Shredder, who reveals his plans to create more mutants. When he exposes himself to the ooze, he mutates into Super Shredder and trys to bury them all but ends up killing himself instead.