John Crankton, a fisherman, is killed by an unseen predator in the bayou. The next day, Sam Rivers, a medical examiner who grew up around these waters, and Mary Callahan, a biologist who feels uneasy in unfamiliar terrain, venture into the marsh to uncover what happened. Sam is at ease in his surroundings, while Mary senses danger around every bend. They soon encounter Elmer noodling for catfish in the swamp canals, and with Elmer’s help they push upriver toward a fishing community.
There they meet Gloria Crankton, John’s wife, and Eliza Crankton, his daughter. Eliza’s semi-boyfriend Dan also lives at the house, and Gloria explains that a strange boat washed up upriver three months earlier after a hurricane, after which odd things have begun to happen around town.
Sam and Mary discover a large fishing boat along the canal and explore its interior while Elmer waits outside. They find the crew’s remains in the hold; upset, Mary clumsily knocks Elmer from the boat and something drags him under. The two flee in the boat, unaware that they have triggered a homing signal on the ship. On the mainland, a team relays the incident to their employer, Jeff, a wealthy bounty hunter.
That night, Roland hears noises from his roof and, when he leans over, an unseen fish leaps up and decapitates him. His wife Bobbi tries to escape on a small boat, but the creature—revealed to be a genetically engineered, humanoid “frankenfish”—flips her into the water and kills her. In the panic, the fish begin destroying boats and boathouses, making safe escape nearly impossible. On a neighboring stilt house, Ricardo bait a large hook with an entire catfish and pull up a massive, air-breathing predator; the monster bites at Ricardo’s legs, and he shoots it in the head, only for a second frankenfish to leap from the water and devour him.
As Mary’s plan remains unrevealed, she dies in an accidental gunfire incident triggered by an explosion that propels a propane tank into the boathouse, sending Eliza into the water. Sam dives in to rescue her, and in the mayhem a frankenfish leaps out and tears off Gloria’s legs. The beast continues its rampage, punching holes in boathouses to sink them.
Jeff and his crew arrive, and the fish turns its attacks toward them, knocking them from the fanboat. With few options left, Sam, Eliza, and Dan join Jeff in pursuing the creature, even as most of Jeff’s team is slaughtered. The trio follows a bloody trail back to the fish’s den, where the monstrous predator is found dead—at least for the moment. Jeff forces Sam at gunpoint to enter first; Sam flees as a third, even larger frankenfish kills two hunters, including Jeff. Dan, Sam, and Eliza hurry to escape on the fan boat, but Dan falls into the mud and is left behind as the fish closes in—while dozens of baby frankenfish emerge from the water, closing in on him. Sam and Eliza share a kiss as they turn back toward safety, hoping to rescue Dan, but the perilous waters remain full of deadly, engineered predators.
