Five years after the events of the first film, Jonas Taylor has been involved in fighting environmental crimes while also helping Mana One in exploring a further deep part of the Mariana Trench where the Megalodon had been found. Following the death of Suyin Zhang, Jonas has been raising her teenage daughter Meiying alongside her uncle and Suyin’s brother Jiuming Zhang, who has acquired his father’s company alongside wealthy financier Hillary Driscoll. Mana One has also been studying an 80 ft (24 m) female Meg called Haiqi, who was discovered as a pup and trained by Jiuming in a reserve in Hainan. Recently, Haiqi has been acting erratically, leading to Jonas being concerned despite Jiuming’s enthusiasm.
Jonas and Jiuming lead a routine submersible exploration to the Trench, with Meiying stowing away to see the trench for the first time. Fellow Meg survivors DJ and Mac observe the group from the Mana One. On their way down, the subs are pursued by Haiqi, who escaped captivity the previous night; the subs dive down through the thermocline to escape, but Haiqi forces her way through it anyway. Two much larger Megs, a massive alpha male and a slightly smaller beta male, appear and mate with Haiqi. While working on an escape plan, Jonas and his team discover an illegal mining operation in a station captained by the mercenary Montes, who has a vendetta against Jonas for his imprisonment some time before. Montes’ crew was hired by Driscoll to covertly use the Mana One’s access to the trench to farm rare earth minerals that could earn them billions. Montes kills his crew in an explosion to cover up their activities, which causes a rupture in the trench and grounds both Jonas’ and Jiuming’s ships.
DJ, Mac, and fellow Mana One analyst Jess discover that the rescue pod has been sabotaged, forcing the crew to use exosuits to walk towards the station in the creature-filled trench, with only Jonas, Meiying, Jiuming and security officer Rigas surviving the journey. Jess and Driscoll reveal themselves to be traitors and attempt to kill the four, but they escape the station in another submersible after a scuffle with Montes, who escapes to the surface through a buoy. Driscoll sends mercenaries to take over the Mana One while Montes surfaces and meets with Jess. As the crew surfaces, they discover the rupture from earlier which leads to several of the creatures, including the three Megs, a swarm of lizard-like creatures known as Snappers and a giant octopus escaping the trench and reaching the surface.
Jonas’ crew meets with DJ and Mac, and Montes focuses the mercenaries on the crew after Jess is devoured by a Meg. Jonas’ team escapes to a nearby resort, Fun Island, to warn them of the approaching creatures. Driscoll, Montes and the mercenaries arrive at Fun Island to eliminate Jonas’ crew, but they are instead attacked by the Snappers, who kill Driscoll and several mercenaries. Jonas’ group splits up to evacuate the tourists as the Megs and the octopus begin their attack. Jonas manages to kill the beta male Meg using an explosive taped to a harpoon before being attacked by Montes, leading both to sail to the beach. The two battle before Jonas knocks Montes into the mouth of the alpha Meg to be consumed. Jiuming creates a bomb out of fertilizer and along with Mac takes over Driscoll’s unattended helicopter to fly towards the beach where Meiying is trying to help tourists.
The octopus takes down the helicopter and Jiuming injures it with his bomb, attracting Haiqi, who engages in a battle with the Octopus and proceeds to kill the beast. As Jiuming swims towards the wreckage to save Mac, Jonas picks up one of the helicopter’s rotors and uses it to fatally impale the alpha Meg through the head. Haiqi heads towards Jonas, Jiuming, and Mac, but Jiuming uses his training signals to divert her attention. Haiqi redirects her attention to a pod of dolphins swimming away. Making their way to the beach, Jiuming reasons that Haiqi escaped captivity because it was mating season, and discusses the possibility that she is pregnant. Jonas decides that it is better not to think about it, and the group celebrate their survival.