An officer of Maine Fish and Game researching American beaver populations is scuba diving in Black Lake, Aroostook County, Maine, when he is savagely attacked and bitten in half by something unseen in the water. A tooth is found in the diver's remains and, as it appears to be a prehistoric fossil, a request is made for assistance to the Natural History Museum in New York City. Paleontologist Kelly Scott (Bridget Fonda) gets the job, mainly because her boss, with whom she has had an office affair, wants her out of his way so that he can pursue another relationship with one of Kelly's co-workers.
Upon arriving in Maine, Kelly informs Fish and Game officer Jack Wells (Bill Pullman) and Sheriff Hank Keough (Brendan Gleeson), who himself witnessed the fatal attack, that the tooth appears to be reptilian in nature, and is not a fossil, but something much more recent. They also meet Delores Bickerman (Betty White), one of few people living on the lake, who claims to have killed her husband.
Later that afternoon, a helicopter arrives at the camp where we are introduced to Hector Cyr (Oliver Platt), an eccentric mythology professor, flamboyant multi-millionaire and crocodile enthusiast who believes, despite Hank's intense skepticism, that the creature doing the attacks is indeed a crocodile. While the four are out exploring the lake, the creature is shown settling under Kelly and Hank's canoe. Hector's radar begins to pulsate as Kelly and Hank are thrown off their canoe and into the water.
That night, due to his antagonistic nature and free spirit, Hector angers Hank and the two get into an argument. After the two are broken up, Kelly tells Jack and Hank that Hector believes crocodiles are godly creatures (since he's never been bitten by one).
The next day Jack and Hector go diving in the lake to find the creature. After the two enter the water, a speaker producing the sound of baby crocs in distress is placed in the water. The creature is shown sneaking up on them. It pulls the boat anchor, but Hank orders his deputy Burke to cut the anchor cable and the boat escapes. Kelly falls overboard, but is saved just in time as the croc was preparing to attack. Jack and Hector come back up separately and while removing the speaker, Burke is attacked by the creature and his head is bitten off.
Hank mourns the deputy and blames himself for his death. Hector's attempts to console him backfire and anger him, and they get into another fight. During the brawl, Hank chases Hector to the lakeside and as the others follow, a grizzly bear appears. Jack pulls Kelly out of the way, but the bear looms over them. Suddenly a giant crocodile leaps out of the water and drags the bear back into the lake. Kelly and Jack share a moment of awkward intimacy as Kelly dresses Jack's cut. Jack, Kelly, and Hank visit Delores again. They find her feeding the crocodile by bringing a blindfolded cow to the edge of the lake. Delores reveals to have been feeding the crocodile for six years prior to it having followed her husband home and to which she also reveals that the crocodile killed her husband, not her. She is placed under house arrest for not telling the police what she knew when they visited her before.
Hector has shared a relationship with one of Hank's deputies and decides to take her on a trip in the helicopter. Hector lands the helicopter in the cove where the crocodile lives. While he is diving it attacks him but he escapes by throwing an inflatable raft which it chases while they escape in the helicopter. On their return, Jack berates Hector for foolishly risking the life of the deputy. Hector sulks in his tent, where Kelly consoles him and he regains his confidence. Jack and Hank plan to allow Florida Fish and Game to kill the crocodile when they arrive, but Hector stops them and 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 of trying this without success, when they are about to give up the crocodile turns up and lunges at the cow. Hector pulls up, loses the cow, and crashes the helicopter into the lake. The crocodile then comes on land and attacks Jack and Kelly, and Kelly is knocked into the lake by its tail, but after some struggling she makes it to the helicopter.
The croc then smashes through the cockpit and gets wedged in, trapping it and allowing Hector and Kelly to swim to the shore. Despite Hector and Kelly's protests to let the animal live, Jack grabs a gun from a deputy and shoots it, but 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 arrive seconds later. They load the crocodile on a truck and take it to Portland, Maine until they can figure out what to do with it. Kelly and Jack also appear to start a relationship, the wounded Jack warmly tells Kelly, "I already miss the crocodile".
The last scene shows Dolores feeding bread crumbs to what appears to be 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