A group of five college kids are forced to match wits with unwelcoming residents when they fly to a "deserted" island for a party weekend.
The movie begins with a couple on a small sailboat who find a small island and begin to look around. The girl sneakily wanders off while the man ties up the boat. She stumbles across a fence and a small compound, but no one seems to be around. She is then attacked by unknown creatures. The man at the boat is startled by her screams.
Cut to a seaplane heading to what appears to be the same island. Matt (Lively) and John (Hudson) are two brothers that are heading to the island for a week of fun and relaxation. The island was owned by their uncle, who built a cabin on it. He recently died, and the island is otherwise uninhabited. The brothers are joined by three friends, Nicki (Rodriguez), Sara (Manning), and Noah (Harper). They fly in on a seaplane, which they moor at a dock near the cabin.
Soon after they arrive, a puppy shows up. The friends take him in to the cabin. Noah goes into the kitchen to get a drink. The puppy follows him in. The puppy then mysteriously growls at him and runs off. Sara and John then follow him out. They are ambushed by an older vicious dog and Sara is bitten by it. The pair manage to get back to the cabin.
The following morning, the boys are in the forest. They bump into the man who came to the island at the beginning of the movie. He is bloody and warns them about the dogs. A pack of dogs attack and eat him. The boys run back to the cabin and tell the girls to come inside. A dog attacks Nicki and John shoots an arrow, wanting to kill the animal, but accidentally impales Nicki's ankle instead. They are soon under siege by more vicious dogs.
The friends decide they must leave the island, but dogs have surrounded the plane. As they have no other way off the island, and no means of communication, they will have to wait out the dogs. A few minutes later, however, they see the plane has detached from its moorings and is drifting toward the ocean. The dogs have chewed through the ropes to force the friends out of the cabin, and when John attempts to swim to the plane the dogs are on the plane and then the dogs attack him. but he manages to swim to the dock then the friends retreat to the house. Sara begins to show distinct canine behavior, such as a ravenous appetite and growling.
Their next idea is to make their way to a storage shed and drive their uncle's car to the training compound, where they believe they can call for help. The car won't start, however, and that night, with no other options, they continue to party. The power goes out, and Noah heads to the fuse box in the basement, where he is killed by dogs who have managed to enter the house. Dogs then find their way into the rest of the cabin, and Matt is bitten. John, Matt, Nicki and Sara have to hide in the attic. There, they discover paperwork relating to the training facility, and learn it was an Army facility to train attack dogs.
The next morning, the dogs have left. Matt and John make another attempt and manage to pop the clutch of their uncle's Mercedes. They went back to pick up the girls but Sara does not want to leave. The dogs attack again, and in fighting one, Sara falls out of the window and impales herself and the dog on a post.
Matt, John and Nicki drive to the facility, which is abandoned. They break in and find out that the dogs were being genetically enhanced. John finds communications equipment, but a power cable on the antenna has been disconnected, so he goes out to fix it. Matt, having been bitten, learns he can sense the dogs, and realizes if they escaped they can get back in. When the antenna is powered up, John is accidentally shocked by electricity, and when he falls to the ground the dogs attack him. Matt shows up with a baseball bat to fight off the dogs, but a power surge has caused a fire in the compound. Nicki realizes the fire is creating a backdraft, and lures in the dogs before exposing them to the fire. The building explodes.
John tells Matt he saw a nearby boat, the same boat the couple brought to the island at the beginning of the movie. When dogs surround them, Nicki shows up in the Mercedes, they jump in and drive off. Because there are so many dogs, they cannot stop the car and get out, so John has Nicki drive the car off the pier. They swim to the boat and sail off.
Thinking they are safe, they wonder if they can make it to medical facilities before Matt and John fall victim to the dog bites. In the last shot, they open the door to the sleeping quarters, and a vicious dog jumps out.