The villainous criminal organization known as the Foot Clan has been terrorizing New York City, led by the ruthless Shredder. Beneath the sewers, the rat sensei Master Splinter (Danny Woodburn) has been training his four sons until they are ready to take Shredder on and become heroes.
Reporter April O'Neil (Megan Fox) pesters a dock worker for information on chemical materials that the Foot Clan may be involved with. Not getting any answers, she and her cameraman Vernon Fenwick (Will Arnett) go into the city to do a puff piece on trampoline fitness. April wants to do better stories, but Vern assures her that some people enjoy these kinds of stores the same way they enjoy foam on coffee.
April learns from the dock worker that something is being brought in by the docks. She rides her bike there at night to find the Foot Clan, led by their lieutenant Karai (Minae Noji), preparing to bring something in. April tries to get footage on her phone, when a shadowy figure shows up and takes out the Foot Soldiers one by one. The figure leaves behind a symbol that April recognizes. She tells her roommate Taylor (Abby Elliott) about this, and also at work to her boss Bernadette Thompson (Whoopi Goldberg), but nobody seems to believe her or care about what she has to say.
We see a man with his hands tied behind his back, and a Foot Soldier trying to attack him, but the man easily takes the Soldier down. This man is The Shredder. Karai reports to him about the vigilante activity, and that these non-human creatures must be stopped.
The NYPD teams up with Eric Sacks (William Fichtner) of Sacks Group Inc to take down the Foot Clan. April finds Sacks at an event, where we learn that her father worked with Sacks on a project before he passed away.
After the event, April and Vern drive home when they see terrorized New Yorkers scrambling all around the streets. April leaves the van to check it out, only to get grabbed by a Foot Soldier and thrown in with other hostages. Karai calls out the vigilantes to show themselves, or the Foot Soldiers will execute the hostages. The Ninja Turtles catch them on their cameras, and them ride the subway to find the Foot Clan and beat them down easily, freeing the hostages in the process. April runs out and climbs a fire escape to find the Turtles on the roof. She snaps a picture, which startles them. She gets grabbed and is confronted by the Turtles, causing her to faint. When she comes to, she meets the four heroes in a half-shell - the leader Leonardo (Pete Plozek), the brainy Donatello (Jeremy Howard), rebellious Raphael (Alan Ritchson), and goofball Michelangelo (Noel Fisher). Donnie wiped April's phone, and Leo hands it back to her, warning her not to tell anybody about them, or they'll find her. Mikey reiterates this, and it's obvious he's attracted to April. The Turtles leave, but April still manages to get a picture of them from a distance.
April runs home and opens a box filled with documents, pictures, and videos on Project Renaissance, what her father and Sacks were working on. April sees a video of her as a kid recording in her father's lab, using a mutagen on the Turtles and Splinter, pre-mutation. She personally named them and fed them pizza, which they all loved. She even recognizes the symbol from earlier as meaning "family."
The Turtles try to sneak back into their lair without alerting Splinter. However, he manages to catch them and punishes them by making them maintain balance on certain items until they tell him why they were out on the streets. Splinter breaks Mikey by tempting him with (what else) pizza. Mikey admits they were out fighting the Foot Clan and when he mentions April's name, Splinter is alarmed and her orders the Turtles to go find her.
April continues digging into the Turtles' past, and she tells Thompson about what she saw the previous night. Unfortunately, this gets her fired. Afterwards, Vern takes her to the Sacks Estate so she can personally ask Sacks about what he and Dr. O'Neil were working on. She shows Sacks the photo of the Turtles, and he takes her into his room to tell her about his past in Japan, being abandoned by his father and learning of a legend about a ruthless warlord in the area. He gives April his card.
April logs onto her computer to find some news on the Turtles in the subway, only to find that Donnie hacked her computer and sent her an address for her to meet them at. She goes alone and the Turtles take her into their lair. There, she meets Splinter, who remembered April before he mutated. He tells her that her father was working with Sacks and Shredder, but he learned that Shredder was planning something evil, and so Dr. O'Neil burned the lab down, at the cost of his own life. April saved Splinter and the Turtles, and she took them to the sewers to be safe. The mutagen later took effect and turned Splinter into a walking and talking rat that raised the Turtles as his sons. The boys were always curious about life above the surface, but Splinter tried to keep them away, and instead taught himself the art of ninjitsu before passing it down to the Turtles. When they were ready, he armed them with their trademark weapons (Leo with his katanas, Donnie with his bo staff, Raph with his sai, and Mikey with his nunchucks). Splinter expresses his thanks to April for protecting them.
Sacks is really working for Shredder, and they come by his armor, which has been given some upgrades. The Foot Clan also manages to track the location of the lair. They infiltrate the place, triggering an alarm that alerts the Turtles. The Foot Soldiers break in with a bomb and blow the place open. The Turtles fight the Soldiers, and Splinter gets in on the action himself. Mikey brings April to a safe spot before returning to fight. Shredder enters the lair, decked out in his armor with multiple knives on each arm. He faces off with Splinter, who dodges Shredder's knives and gets a few good hits in. Splinter shuts the doors to protect his sons, but they lift them up in time to see Shredder grab Splinter and hold him before the Turtles, threatening to kill him if they don't lay down their weapons. They do so, but Shredder still hits Splinter hard enough to take him out, while the Soldiers cattle-prod the Leo, Donnie, and Mikey, capturing them and then blowing the lair up. Raph emerges from the rubble and goes with April to take Splinter to rest. He pleads with Raph to save his brothers and stop Shredder. Raph gets ready to spring into action.
April calls Vern to take her and Raph to the Sacks Estate again. Vern sees Raph and, although he's shocked, he complies and drives them. In the laboratory beneath his home, Sacks holds Leo, Donnie, and Mikey in cages, trying to extract their blood that contains mutagen. His and Shredder's plan is to infect the city with a toxin that would quarantine the city, and then seize control over everyone with the mutagen to use as a cure. Outside, Vern rams through the gate, running over Foot Soldiers. Raph busts out of the van to go find his brothers. April and Vern follow. Raph fights Shredder on his own while April tries to free the others by giving them an adrenaline injection. This allows them to bust out and help Raph fight Shredder before the villain flees.
The heroes hijack a truck with Karai and the Foot Soldiers chasing after them. The Soldiers hit the truck with an RPG, causing them to slide down the mountain. The Turtles slide down the mountain on their shells, taking out the Foot Clan trucks by slamming into them or flipping them over. Donnie calculates a big drop happening momentarily. Karai hooks onto Leo as he tries to save April and Vern, causing her truck to tumble over and crash into a tree. Raph pulls Leo, April, and Vern up in time. They then head over to the city to stop Shredder.
Shredder and Sacks make it back to Sacks's tower to release the toxin. April and Vern go look for the mutagen while the Turtles take Shredder on. They charge in with Mikey yelling "Cowabunga!" The Turtles gang up on Shredder, but he proves a tough foe to beat. Meanwhile, April manages to secure the mutagen as Vern knocks Sacks out, even after Sacks shoots Vern in the arm. The Turtles then band together with a maneuver that allows them to push Shredder off the roof. Donnie goes to stop the toxin's release as Shredder pulls himself back up. Leo, Raph, and Mikey continue to hold him off, and Donnie is able to stop the release with a second to spare. Shredder then tries to knock the top of the tower down, and the Turtles try holding it back April gets to the roof and shows off the mutagen to Shredder to distract him. The top of the tower comes crashing down as Shredder lunges at April and throws them both off. They hang on for dear life, and the Turtles try to save April. Shredder tries to finish them off, but Leo throws his katana at him, causing Shredder to lose balance and fall to the ground. The top of the tower comes lose, taking April and the Turtles with it. Raph admits his brash behavior was out of fear for his brothers, and he admits he loves them, right before he realizes they landed safely. Mikey notices he's crying, but Raph brushes it off. They return to the sewers. The citizens then crowd around Shredder, who slightly moved his hand with mutagen on his fingers...
The Turtles get some mutagen to revive Splinter. He is proud of his boys. Later, April meets up with Vern, who is showing off his new car. The Turtles show up in their own vehicle to thank April for her help. Mikey then accidentally launches a rocket that blows Vern's car up. The Turtles offer to give them a lift, but April says they'll take the subway. As they drive away, Mikey sings "Happy Together" to April. She smiles.
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