Eight years following the events of the original film, Jonas Taylor, portrayed by Jason Statham, has dedicated his life to combating environmental crimes while assisting Mana One in exploring the more profound depths of the Mariana Trench, where the colossal Megalodon once roamed. Tragically, after the passing of Suyin Zhang, Jonas has taken on the responsibility of raising her teenage daughter, Meiying (Shuya Sophia Cai), along with her uncle, Jiuming Zhang, played by Jing Wu. Jiuming, now at the helm of his father’s company, has enlisted the support of the affluent financier Hillary Driscoll (Sienna Guillory).
Within this quest, Mana One has been studying a remarkable 80-foot female Meg named Haiqi, who was discovered in her infancy and trained in a reserve in Hainan by Jiuming. Recently, however, Haiqi's behavior has been increasingly erratic, which raises concerns for Jonas, despite Jiuming's enthusiasm and optimism regarding the situation.
During what should have been a standard submersible exploration of the trench, Meiying unexpectedly sneaks aboard to witness the trench's wonders. Observing from a distance are fellow Meg survivors DJ (Page Kennedy) and Mac (Cliff Curtis). But things take a dire turn when Haiqi, who managed to escape captivity just the night before, pursues their subs. Despite the crew's efforts to dive deeper through the thermocline to evade her, Haiqi successfully breaks through.
Things worsen when two considerably larger Megs appear—an imposing alpha male and a slightly smaller beta male—which join with Haiqi in a mating display. As Jonas and his team formulate their escape plan, they stumble upon an illegal mining operation run by mercenary Montes (Sergio Peris-Mencheta), who harbors a grudge against Jonas due to past imprisonment. In a shocking turn of events, Montes eliminates his own crew in an explosion, attempting to conceal their illicit operations and causing a catastrophic rupture in the trench that jeopardizes both Jonas and Jiuming’s vessels.
Meanwhile, DJ, Mac, and analyst Jess (Skyler Samuels) discover that their rescue pod has been sabotaged, forcing the remaining crew members, including Jonas, Meiying, Jiuming, and security officer Rigas (Melissanthi Mahut), to don exosuits and navigate their way through the creature-infested trench to the station. During this perilous journey, Jess reveals her betrayal and attempts to obliterate the quartet. Yet, they manage to escape in another submersible after a fierce struggle with Montes, who makes his own escape via a buoy.
As the crew manages to surface, they encounter the aftermath of the earlier rupture, leading to an outbreak of monstrous creatures, including the three Megs, a vicious swarm of lizard-like creatures dubbed Snappers, and a massive octopus that emerge from the depths of the trench.
Jonas’ team reunites with DJ and Mac, only to find that Montes is now directing mercenaries toward them, having witnessed Jess being devoured by a Meg. With the threat intensifying, Jonas leads his group to Fun Island, hoping to warn tourists of the impending danger. However, Driscoll and the mercenaries arrive with lethal intent, only to find themselves ambushed by the Snappers, leading to Driscoll's demise and chaos among the mercenary ranks.
As the Megs and the octopus begin their assault on the resort, Jonas takes matters into his own hands, using explosives to eliminate the beta male Meg before engaging in a fierce battle with Montes. Their clash culminates in Montes meeting his end as he is cast into the jaws of the alpha Meg.
In a moment of ingenuity, Jiuming combines fertilizer to create a bomb and, alongside Mac, hijacks Driscoll’s helicopter in a valiant attempt to save Meiying and the remaining tourists. The octopus, however, dismantles their aircraft, but Jiuming manages to wound it, drawing Haiqi into the fray. A fierce battle ensues between Haiqi and the octopus, culminating in Haiqi's victory.
As chaos reigns, Jiuming swims towards the wreckage to save Mac, while Jonas uses a helicopter rotor to skew the alpha Meg through the head, sealing its fate. As they reach the safety of the beach, Jiuming speculates on Haiqi potentially achieving pregnancy due to her recent mating, prompting Jonas to dismiss the thought for now. Eventually, they celebrate their survival, thankful for their escape from an unfathomable nightmare.
