When Shredder plans to create an army of mutants, the Turtles must rely on the help of the Pulverizer, who was recruited into the Foot (to be expendable) and volunteers to gather information on the inside on their behalf. When he agrees to be a test subject for a stolen supply of Kraang Mutagen, the Turtles rescue him, but not before he recklessly gets himself mutated.
Narrowly escaping from the Shredder and the Kraang, the turtles, April, and Casey take shelter at April's family farmhouse upstate to recover and figure out how to stop the Kraang. The turtles deal with not having Splinter around and the possibility of Leo not making a full recovery, and a mysterious creature stalks the group.
Donnie experiments with April's fragment of the mystical Sol Star (which she is becoming quite obsessed with, due to its mighty power drastically strengthening and further developing her psionic abilities), but accidentally supercharges it with electricity, that stirs sudden sentience and autonomy in the crystal fragment. It then uses this to bring four of the main characters from Mikey's favorite comic book to life. Mikey easily befriends the heroes Wingnut and Screwloose, and he and Casey join them in stopping crime. But when they tell the two superheroes about the fact that they're fictional characters, and show them the Soul Star, it causes Wingnut and Screwloose to transform into insane monstrous forms. Meanwhile, Donatello becomes incessantly worried that the Sol Star fragment is affecting April's mental stability.
A futuristic New York City is barraged by mutant criminals and only the turtle team can take them down in the series premiere of shorts in which famous writers and directors in the animation industry tackle "Teenage Mutant Ninja Turtles" tales.
In an alternate, apocalyptic future that takes place fifty years later, all humans and most of the mutant population have been wiped out, due to an extremely powerful mutant explosion that had mysteriously occurred through unknown means. Only a weathered Raphael, who has most of his childhood memories lost to him, and Donatello (whose consciousness has been transferred into Metalhead) have been traveling throughout the Impossible Wasteland trying to save alive while being pursued by the Verminator and his bikers. Befriending a female meerkat warrior named Mira, the last of her tribe, who harbors the secret to "Paradise" and that she must find a wise turtle called "the Holy Chalupa."
Raphael, Donatello and Mira continue to be trapped by constant sandstorms throughout the desert, but are saved by none other than Chompy Picasso, whose physical self has grown considerably over the decades. On their way, they manage to find "the Holy Chalupa" who is, in truth, an elderly thin Michelangelo himself. He takes them to his home of pizza, where Ice Cream Kitty waits. While, the three Turtles are catching up and trying to accept the loss of their leader and eldest brother Leonardo, they are all attacked by Verminator Rex who abducts Mira but is followed by an angry Raphael.
Still trapped in "the Pit", Raphael manages to defeat his two opponents and is hailed as leader of both tribes by the crowd. Aided by Mira, Mikey and Chompy, they flee in search of "the Green Paradise", but they end up having to deal with Leonardo, who ended up having his body undergo a second mutation and his mind scarred by the mutagen bomb, and is now the evil leader of the Wasteland, Maximus Kong.