A 3-headed great white shark attacks an atoll where a group of teenagers are partying, killing all of them except one, Mark, who was on a buoy while the rest of the teens were at the beach. The shark then proceeds to attack the Persephone, an underwater research facility studying the Pacific Garbage Patch. The resulting damage causes the facility to explode, killing everybody inside. However, marine biologists Ted Nelson and Laura Thomas escape, as well as a group of activists touring the lab consisting of Greg, Ryan Bennett, Omar and Alison, and college graduateMaggie Peterson, who was applying for a job at the facility, and is also Greg's ex-girlfriend. The island the facility is based on begins to flood, and the group is forced to swim out to the activists' boat as a result, Laura and Omar are eaten in the process. The others reach the boat, the shark follows them as they drive. Ryan manages to contact fisherman Max Burns over the radio, and asks for help. Burns is hesitant to believe them but reluctantly agrees to help them. The shark begins to head toward a party boat carrying teenagers. The group attempts to warn them but they're too late, as the shark consistently rams into the boat, knocking numerous people into the water where they're eaten. The group manages to board the boat in order to help injured passengers, and Maggie and Nelson are enlisted as help by passengers Stanley and Rosemarie Grant to help find Rosemarie's boyfriend Howard, who had disappeared into the abandoned dining area during the chaos. Maggie, Stanley and Nelson find him, and make their way top deck, although, in the process, the shark jumps onto the back of the boat, and eats Nelson. The group realizes they can no longer stay due to the ship sinking, and board the activists' boat with Stanley, Rosemarie, and Howard in tow. However, Ryan stays behind, and attempts to kill the shark by jumping onto its back with an axe. He manages to clip onto the back of the shark, and it soon kills him in retaliation. Running low on fuel, the group is forced to stop at the atoll that the shark attacked earlier. Meanwhile, Burns, and his two men attempt to kill the shark, Burns' men are killed in the process. Burns manage to decapitate the shark's middle head, seemingly killing it. Burns finds the rest of the group, surprisingly the shark recovers, grows three more heads in place of the middle head, and eats Burns. Traumatized by Burns' death, the group runs inland, where they meet Mark. Maggie theorizes that the shark is attracted to pollution, and that the heads are becoming more aggressive with each other. The group finds two motorboats, and begin to drive away from the island, the shark attacks one of them carrying Alison, Rosemarie, Howard and Mark, and kills all of them. Meanwhile, Maggie, Stanley and Greg manage to attract the shark's attention by throwing bags of garbage into the water, Stanley's hand is bitten off in the process. Losing faith, Stanley sacrifices himself by allowing the shark heads to fight over him, resulting in three of the shark's heads getting bitten off, and the shark itself dies of blood loss. Maggie and Greg rekindle their relationship as a helicopter arrives to rescue them.
A third film in the series, 5-Headed Shark Attack, was released on Syfy on July 30, 2017, and a fourth film, 6-Headed Shark Attack, was released on August 18, 2018.