After the defeat of their old arch nemesis, The Shredder, the Turtles are needed more than ever, but Raphael, Donatello, and Michelangelo have become lost and direction less. Leonardo has gone to Central America, on the orders of the martial arts master and father figure Master Splinter, for training. Donatello and Michelangelo have started small businesses in Leonardo's absence. Meanwhile, strange things are happening in New York City. An army of ancient creatures threatens to take over the world and the Turtles must unite again to save it.

It all begins when young Will Stronghold, the son of the two famous superheroes: Steve and Josie, A.K.A. the incredibly strong, seemingly invulnerable Commander and and the high-speed flying Jetstream. However, Will does not actually know if he has any powers of his own, and has not told his parents this. He and his best friend, Layla are facing their first day of a secret school in the clouds like none on earth: Sky High, the first and only high school for kids with super-human powers going through crime-fighting puberty. But with no apparent superpowers of his own, however, Will seems destined to grow up a mere sidekick. But as he discovers his true strengths, he'll also learn that it takes loyalty and teamwork to truly become a hero!

In the not-so-far future the polar ice caps have melted and the resulting rise of the ocean waters has drowned all the coastal cities of the world. Withdrawn to the interior of the continents, the human race keeps advancing, reaching the point of creating realistic robots (called mechas) to serve them. One of the mecha-producing companies builds David, an artificial kid which is the first to have real feelings, especially a never-ending love for his "mother", Monica. Monica is the woman who adopted him as a substitute for her real son, who remains in cryo-stasis, stricken by an incurable disease. David is living happily with Monica and her husband, but when their real son returns home after a cure is discovered, his life changes dramatically.

Sam Brenner, Will Cooper, Ludlow Lamonsoff, and Eddie "The Fire Blaster" Plant all played classic arcade video games as teenagers. But now they have to use their skills to try to save the world from aliens. The aliens watched video feeds that they thought was a declaration of war. So they send down the classic arcade games to destroy earth. They also get help from a military specialist. They have three lives and if all three get used then earth will be destroyed, and every time they lose a live the aliens take someone's life. Who will win, us or the aliens? It's an all-out battle to save our planet and everyone on it.