In the midst of an intense training session with Master Splinter, the Teenage Mutant Ninja Turtles are attacked by Mouser robots. With their lair destroyed, the Turtles must search for their Master and find a new home.
The Turtles discover Stocktronics CEO, Dr. Baxter Stockman. Donatello repairs a disabled Mouser and the Turtles track it through the sewers, where they stumble upon April O'Neil, a young apprentice fleeing from the wrath of Dr. Stockman.
After fainting from their initial encounter, April O'Neil wakes up in the Turtles' lair. It is there April learns of the Turtles' origin, and they all agree that Baxter Stockman and his rampaging Mousers must be stopped.
During a sparring session, Raphael lets his anger get the best of him and almost hurts Michelangelo seriously. He decides to go topside and meets someone filled with a lot more anger than him: a streetwise vigilante named Casey Jones.
A small-time thief goes on a crime spree when he stumbles upon an artificial intelligence made up of nanotechnology. When the crook and his ward reach April O'Neil's new antique shop, they face off against Casey and the Turtles.
After a blackout knocks out the lights in the lair, the Turtles go topside to investigate. Once above ground, the Turtles encounter the mysterious Foot Clan gathering artifacts from around the city.
Casey Jones becomes an unwanted guest in the Turtles' lair, so Raphael takes him topside to get some much-needed air. During a routine skirmish with the Purple Dragons, Raph and Casey encounter the Foot Tech Ninja. Raphael is kidnapped.
Angel, a girl Casey knows from the neighborhood, is going through her initiation to join the Purple Dragons. Casey fears her going down the wrong path and tries to stop her from joining the gang with the help of the Turtles.
When homeless people start to disappear mysteriously, the Turtles set out to investigate. Their search leads them to a garbage-filled island where the homeless are being used as slaves by the villainous Garbageman.
Leonardo meets Oroku Saki, leader of the Foot Clan. They soon learn the true nature of the Foot, their leader, and the significance of their emblem. Oroku Saki reveals himself as the Shredder. The Turtles soon find themselves outmatched.
Concurrently, Master Splinter searches for his sons and after finding them prepares a counteroffensive. During another encounter with the Shredder, the Turtles are cornered, but Splinter intervenes and faces off against the Shredder.
Michelangelo yearns to use his abilities to help the citizens, leading him to create his alter ego: Turtle Titan. While attempting to team up with his inspiration, Silver Sentry, Mikey must battle his hero's arch-nemesis, Dr. Malignus.
When Don's examination of some mysterious crystals attracts the attention of a subterranean monster, the Turtles underground exploration unearths a Foot Genetics Lab.
After discovering an abandoned underground Foot Genetics Lab and being attacked by once-human Digging Creatures, the Turtles assist those very creatures in trying to repair a Force Field to protect them against mindless beasts.
The source of the crystals are found in an ancient subterranean city. The city is inhabited by the sole survivor of an ancient race, who he claims wanting to return the creatures to their original form, his true intentions remain unknown.
With the Foot scouring the sewers, the Turtles move in with April. When Donatello enters the basement, he meets April's tenant Kirby, an artist who has the power to open doorways to other dimensions.
Leonardo encounters a legion of Foot Ninja and Hun. A thunderstorm develops not long before Leo encounters a new foe, the Foot Elite. As he becomes overwhelmed, Leo witnesses the return of an unexpected enemy: The Shredder.
After being thrown into April's apartment, Leonardo lies unconscious while his brothers and Splinter defend themselves against waves of attacking Foot Ninja. As the Turtles and their allies are retreating, Shredder blows up the building.
After getting out of the building just before the explosion, the group head to the old farmhouse of Casey's grandmother. As Leonardo lies unconscious, each member of his family tells Leonardo a tale of his early adventures as a child.
Still recuperating at the farmhouse, the Turtles try to keep themselves busy. Raphael helps Leonardo forge new katanas while Michelangelo, Donatello, and Casey deal with Abigail Finn, who hopes to catch the "Green Man of the Woods".
The Turtles return to New York City and are preparing for the battle against the Shredder. Thinking that he has destroyed his enemies, the Shredder is unprepared for a surprise attack on his headquarters by the Turtles and Splinter.
The Turtles work their way up to the Shredder. They encounter clones, the Foot Mystic Ninjas and an exosuit-clad Baxter Stockman, who wants to get revenge on all of them. The Turtles and the Shredder are forced to work together.
The Turtles then continue to fight the Shredder, with master Splinter being wounded. With help from a mysterious group of warriors known as the Guardians, the Turtles defeat the Shredder but find that Master Splinter has disappeared.
With the Shredder defeated, the Turtles turn to a new problem: Master Splinter is missing. Angry and confused, Raphael heads out to find him, only to be thrust into a solo adventure helping a headstrong kid, Tyler, against mobsters.
After a frustrating search for Splinter, the Turtles' suspicions turn towards the Guardians. This suspicion leads them to an austere building with the company name TCRI - the name on the canister of ooze responsible for their mutation.
The Turtles manage to infiltrate the TCRI building, discovering that there is more to the building than meets the eye. They manage to find Splinter in a stasis tank but soon find themselves transported to a place unknown.
