After years of living apart, the four ninja turtles have lost their unity and purpose. Leonardo has been away on a training mission to become a better leader, while Donatello now works as an IT specialist, Michelangelo runs a party entertainment business, and Raphael patrols the city at night as a vigilante. The turtles' old enemy, the Foot Clan, has also disintegrated, and New York City has grown used to a life without its reptilian heroes.

As Leonardo returns to the city, he finds tension and estrangement among his brothers, who have drifted apart without a common enemy to fight. Simultaneously, wealthy industrialist Max Winters is amassing an ancient army of monsters to fulfill a mysterious agenda. As supernatural events unfold, the turtles must overcome their differences and face the growing threat to the city, with the aid of their wise master Splinter, the determined reporter April O'Neil, and her boyfriend, the adventurous Casey Jones. The brothers confront their own personal struggles as they prepare to band together once more to tackle this new menace.