In Aroostook County, Maine, Marine fish and Game officer Walt Lawson is suddenly attacked and bitten in half by an unknown beast in Black Lake. Sheriff Hank Keough, Fish and Game officer Jack Wells and American Museum of Natural History paleontologist Kelly Scott go to the lake to investigate with mythology professor/crocodile enthusiast Hector Cyr joining them.
Eight years after the events of the first film, Aroostook County, Maine researcher Frank Mills, and his friend Tillman, are collecting specimens at Black Lake, although a crocodile soon pulls Tillman into the water, and kills him. Frank reports this to sheriff James Riley, showing him Tillman's severed body parts. James, Frank, and wildlife officer Emma Warner venture out onto the lake, where they find more of Tillman's body parts. Meanwhile, three friends, Mike, Edie, and Sharon are killed by a crocodile while swimming in the lake. James, Emma and Frank stop at the house of Sadie Bickerman, a woman who has allegedly been feeding the crocodiles, to interrogate her, although she refuses to let them in the house. After they leave, Sadie tricks a photographer into being killed by the crocodiles. James, Emma and Frank go out on the lake again, although a crocodile destroys their boat, forcing them onto shore. A poacher named Struthers and his assistant Ahmad, soon land their plane on the lake, hoping to kill the crocodiles after getting a tip from a local.
A year after the events of Lake Placid 2 at Black Lake, in Aroostook County, Maine, young couple April and Jason go skinny dipping and are attacked and eaten by a group of baby crocodiles. Meanwhile, at the house of the deceased Sadie Bickerman, her nephew Nathan, his wife Susan, and their son Connor, are cleaning out the house so they can sell it. However, Sheriff Tony Willinger soon arrives and convinces Nathan and Susan not to sell. Connor chases an escaped pet lizard down to the lake where he encounters the baby crocodiles, and begins to secretly feed them.
The film starts with a scene inside of a destroyed supermarket, Reba seems to be killed by a crocodile from the Lake Placid 3 but unconsciously survived, then she throws the knife to the last surviving crocodile. Reba, now a United States Environmental Protection Agency Agent, with Dennis and Sheriff Theresa Giove, venture to Black Lake and neutralize an infant crocodile with a tranquilizer. They meet Lieutenant Ryan Loflin on land and drive towards a ten-thousand volt fence built by the Army Corps of Engineers.
In Black Lake, Maine, mercenary Beach and Jim Bickerman (who survived from an attack by a crocodile in ''Lake Placid: The Final Chapter'', now lost his eye, hand and leg, replaced with a eye patch, hook and wooden leg) capture a female giant crocodile. They take it back to their truck, where two scientists crossbreed with a female giant anaconda to perfect the Blood Orchid serum. However, the crocodile escapes and kills a scientist, and frees the female and two male anacondas before causing the truck to explode and destroying part of the electric fence, keeping the crocodiles in Black Lake, though Beach, Bickerman, and the remaining scientist survive. However, a small group of crocodiles also escape.