Four turtles fall into the sewers and are befriended by Hamato Yoshi a Japanese man sent to New York who was forced to live in the sewers. One day he sees a strange green glow which transforms the four turtles into human-like creatures. Hamato (now Master Splinter) changes into a giant rat from the green glow and teaches the turtles the skills of the ninja as they team up with news reporter April O'Neil to battle against Yoshi's arch enemy Shredder and Krang, an alien warlord from Dimension X.
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The Turtles are working on once and for all ridding themselves of their mutations, Donatello makes use of a Virtual Reality Program to test out the effects of a potential cure he has created using the Vortex Crystals.
Having recaptured the mutated Leonardo, the Turtles quickly restore him to normal using the vortex crystal technology. At first, it seems that the experiment has worked this time, but soon Leonardo's foot starts glowing, he still has the disease, and which means it's only a matter of time until he mutates once more.
Mungg informs Dregg that he came across two individuals who claimed they were old acquaintances of the turtles: Shredder and Krang!
The Turtles', Shredder's and Krang's battles skills, powers, and memories are absorbed into Dregg.
Dregg and his crew plan an invasion Earth to make it his new home base, but first he has to get his transporter chip back from Shredder.
Dr. Alvin Huxley has demonstrated his breakthrough invention: a computer that thinks as fast as a human mind. The Globfather is on Earth and wants to get the protein computer for someone who is willing to pay a lot for it.
With the city breaking apart, the Turtles head to the street to investigate and see the Dreggnaut appear in the sky. With Mung's help, Dregg reprograms the transporter to open a warp in space.
Dreeg is holding a meeting with this world's strongest and most feared combatants, and promises wealth and power to any who are able to last 90 seconds with the Turtles.