In Lincoln County, Maine, a marine Fish and Game officer is attacked and bitten in half by something unseen in Black Lake. Sheriff Hank Keough (Brendan Gleeson), Fish and Game officer Jack Wells (Bill Pullman), American Museum of Natural History paleontologist Kelly Scott (Bridget Fonda), and mythology professor/crocodile enthusiast Hector Cyr (Oliver Platt) go to the lake to investigate.
A series of strange events occur, including Kelly and Hank's canoe mysteriously flying into the air and flipping, the discovery of a severed toe and a severed Moose head, and the decapitation of a Fish and Game deputy. Later, as Hank and Hector argue, a giant saltwater crocodile leaps out of the water and drags a nearby bear into the lake. Jack, Kelly, and Hank visit Delores Bickerman (Betty White), one of few people living on the lake. After finding the deputy's severed head, they witness her feeding a blindfolded cow to the enormous crocodile. Delores reveals that she has been feeding the crocodile for years after it followed her husband home. It eventually killed him. She is placed under house arrest for initially lying to the police.
Hector decides to take one of Hank's deputies (Meredith Salenger) on a trip in the helicopter, and lands the helicopter in the cove where the crocodile lives. While he is diving, it attacks him, but he escapes. Jack and Hank plan to allow Florida Fish and Game to kill the crocodile when they arrive, but Hector suggests instead that he lure it out of the water and drug it. Jack reluctantly accepts the proposal, and they use one of Delores' cows, dangled from the helicopter, as bait. After a few hours, the crocodile lunges at the cow. Hector pulls up, loses the cow, and crashes the helicopter into the lake. The crocodile comes on land and attacks Jack and Kelly. Kelly is knocked into the lake, but she makes it to the helicopter just in time.
Despite Hector and Kelly's protests to let the animal live, Jack grabs a gun and shoots it. The gun is revealed to be a tranquilizer rifle. As Hector comes out of the water, a second crocodile attacks him, but Hank blows it up with his grenade launcher. Florida Fish and Game officers arrive seconds later. They load the crocodile on a truck and take it to Portland, Maine to figure out what to do with it. The last scene shows Delores feeding bread crumbs to many baby crocodiles, implying the two adults were a mating pair. During the end credits, the surviving adult crocodile is seen tied to the back of a flat-bed truck, speeding down a road