Shortly after the events of the third film, Reba Yancy Butler is revealed to still be alive and she kills the last remaining crocodile in the supermarket.
Two years later, Reba, now an EPA agent, returns to Black Lake with Dennis and Sheriff Theresa Giove Elisabeth Röhm to neutralize a crocodile hatchling with a tranquilizer. They meet lieutenant Ryan Loffin Paul Nicholls on land and drive toward a ten-thousand-volt fence built by the Army Corps of Engineers. Dennis and a poacher named Jimmy Bickerman Robert Englund sneak into the lake to steal crocodile eggs, but they are attacked by crocodiles. Max, Ryan's son Benedict Smith, hears their screams, but is attacked and dragged away by a crocodile.
Theresa's daughter, Chloe Poppy Lee Friar, and her friend Elaine Caroline Ford join the Marshfield Swim Team in a tour bus, which mistakenly goes through the gate (left open by Max) of the electric-fenced park toward Black Lake instead of Clear Lake due to the driver not paying attention, and the swim team spends the night there, sharing tense conversations. Gus Kitodar Todorov, the bus driver, uses the lake as a bathroom, spying on two girls playing in the water, and is killed by a crocodile after the girls leave the water.
The next morning, with the police on alert, Ryan, Theresa, and Reba search; the swim team decides to ride the lake with jet skis, and one of them, Joey Peter Ladjev, falls off the jet ski. He is attacked in the water by a swarm of crocodile hatchlings and killed. A student on the beach is dragged by a crocodile into the water, and another is slain while trying to enter the bus. The other students and Coach Macklin Sewell Whitney make it safely inside the bus before further attacks. Chloe, who has wandered off in the woods, meets Max, who survived, after he fell off a resting platform on top of a tree.
The team finds a skeletal part of a crocodile from a crocodile carcass. The swim team continues to run through the woods until they find an abandoned camp and a smaller crocodile. The group flees separately, and Brittany Scarlett Hefner steps into a trap on a rope, and her head is severed by the crocodile, leading to her demise. Chloe falls into a hole, is trapped, and battles with another crocodile. Max distracts the crocodile with a rock, and Chloe subdues it by hitting it with an unloaded gun. The team finds the injured Dennis while Chloe retrieves a cell phone from the crocodile's mouth, which she uses to call her mother. Max dispatches a rope to pull Chloe out of the hole as the crocodile awakens.
The team makes it safely to land, but Dennis is pulled under the bus and killed by a crocodile. The remaining swim team and Max encounter Jimmy, who “forcefully” encourages the kids to board his boat. Coach Macklin refuses to go into the water and is killed by a crocodile. The students and Max are taken hostage by Jimmy. They make it back to land and are taken to Sadie Bickerman's abandoned cabin, where he has them stay in. Jimmy then finds a nest of eggs by the shoreline.
The team finds Tina, one of the students, by the electric fence while Jimmy steals the eggs from the nest and stows them away in his satchel. Elaine finds one room of the cabin full of flesh and blood and is attacked by the crocodile in it. They reunite with the team while Reba accuses Jimmy of his actions. Jimmy takes Max hostage to lead the way out while a crocodile breaks free from its chains and takes a boat with it. Drew Daniel Black is devoured as he tries swimming towards the boat while Max yells for him; Ryan uses the distraction to knock out Jimmy. The others retreat towards the electric fence. Theresa dodges a charging crocodile, causing it to crash into the fence and become electrocuted to death.
By next morning, Jimmy awakens and, after discovering that the eggs are all crushed, taunts the last crocodile. He tosses his satchel and appears to be devoured as the crocodile latches on to his leg. An ambulance arrives to support the survivors by the electric fence. Theresa and Ryan passionately kiss. In the end, a woman jogging through the woods thinks the lake is now crocodile-free, but is killed by the last crocodile that still remains.
