Sheriff Julie Forrester (Elisabeth Shue) of Lake Victoria, Arizona is preparing for Spring Break, the small town's biggest week of the year when thousands of college co-eds come for a drunken, sex-filled, debaucherous weekend on the historical lake. Unfortunately, a new group will be joining the party this year. When a local fisherman (Richard Dreyfuss) accidentally causes the opening of an underwater fault line, a pre-historic species of piranha are released into Lake Victoria.
But Julie has her own problems at home. Julie's son Jake (Steven R. McQueen) has been drawn into the spring break madness when his old flame Kelly (Jessica Szohr) shows up for the weekend. Jake and Kelly are invited to join Derrick Jones (Jerry O'Connell), the owner of a soft core porn site called Wild, Wild Girls along with his beautiful models Danni and Crystal (Kelly Brook, Riley Steele) and his bumbling cameraman Drew (Paul Scheer) as they take a trip on Derrick's yacht around the lake for some raw footage. Julie has requested that Jake watch his two younger siblings, Laura and Zane, for the weekend while she is busy tending to the thousands of party-goers. Jake, obviosuly more interested in the trip with Kelly and Derrick, offers his allowance to Laura and Zane in exchange for them staying at home, staying out of trouble, and lying to Julie about Jake babysitting them.
After discovering the mangled body of the fisherman, Julie and Deputy Fallon (Ving Rhames) decide to seek further help from a team of scientists led by Novak (Adam Scott). But when Novak's team swims down into the underwater cavern and are both mangled by the piranha, Julie, Fallon, and Novak take one of the prehistoric fish that they caught to local pet store owner Mr. Goodman (Christopher Lloyd) who, while a quack, is an expert on fish. Mr. Goodman informs the group that this "particular type of piranha" has been thought to be extinct for a very long time and that once one makes the first kill, the pack will be drawn out. Julie decides the best course of action is to close the lake.
Meanwhile, Laura and Zane have stranded themselves on a sandbar after trying to go on a fishing trip, disobeying Jake. Jake on the yacht, being urged by Danni, has been courting Kelly, trying to rekindle what they once had.
The piranha are out. They've begun devouring divers, swimmers, and parasailers. Jake and his group have unknowingly had several close calls. Julie and Fallon go out on the lake to try and push the spring break-ers out of the lake, but the thousands of drunk, horny 20 somethings play off the cops' warnings and continue the party. But soon, the piranha attack. As the pack of piranha swim into the center of the party, the panicked partiers are being devoured. Its a feeding frenzy. Hundreds of co-eds are being mangled by the blood-thirsty piranha. Boats are overturned, the floating stage crumbles to peices. Its a massacre. As Sheriff Julie quickly pulls injured college co-eds out of the bloody waters she recieves a phone call from Jake who has recently found Laura and Zane and gotten them onto Derrick's boat. Derrick's yacht is stuck and sinking after a crash that caused Drew, Crystal, and Derrick to fall overboard and get devored by the piranha. As the boat sinks, Kelly is stuck in the lower compartment of the boat as Jake and Danni try to rescue her.
Julie rushes out of the center of the massacre with the help of Novak to save her kids and the other survivors on Derrick's yacht. Deputy Fallon rushes into the lake to help save the wounded college kids and grabs the motor off of a nearby boat, telling the piranha to "chew on this muthaf**kas" as he slices them apart, but unfortunately, the piranha swarm him and take him down. Once Julie and Novak get to Derrick's boat, the water is rising and piranha are in the boat with Kelly who is trying to fend them off. Julie ties a rope connecting Novak's boat to Derrick's yacht to get the survivors across. Julie take Laura, Zane, and Danni across first, but unfortunately Danni is attacked and falls into the water, devorued by the piranha. But once Julie and the kids get across, Jake unties the rope from the boat and ties it to himself as he dives into the water, saving Kelly, blowing up Derrick's yacht and all the surrounding piranha as Novak drives his boat away, pulling Jake and Kelly to safety. But just as the group begins to celebrate, Mr. Goodman calls Julie to tell her that the piranha she brought to his shop was a baby and that there are bigger piranha out there. Novak looks at Julie questioningly, and then a huge piranha (perhaps the mother) leaps out of the water and eats Novak.