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The movie opens with a pair of middle-aged men walking through some kind of facility discussing mundane details about marriage and potential children, while a younger woman in a lab coat is trying to inform them about an incident at the Stockholm facility. The two men are not particularly concerned about what she is telling them. They mention that the facility in Japan will get the job done, and that their U.S. facility usually comes in second place. As they board a golf cart and drive off, the younger of the two men invites the older one to come over to his house for the upcoming weekend.
The scene shifts to a room in a college town where Dana (Kristen Connolly) and Jules (Anna Hutchison) are talking about school. Apparently, Dana had an affair with one of her professors and it ended badly. Jules's boyfriend Curt (Chris Hemsworth) walks in and throws a football at the girls. It flies out the window and Curt's friend Holden (Jesse Williams), a fix-up for Dana, catches it down below. The guys are there to pick up the girls for a long weekend at a lakeside cabin that Curt's cousin owns. Dana finishes packing and they all go downstairs to pack up the RV. They are about to leave when their friend Marty pulls up in his car smoking pot from a huge bong that converts into a travel mug.
We cut back to video screens in the previously seen facility where the two middle-aged men, Sitterson (Richard Jenkins) and Hadley (Bradley Whitford), are watching all of this happen. Apparently, they have been drugging the kids through various means (hair dye for Jules, Marty's stash, etc.) but they don't say why.
The group is close to the cabin when they stop for gas and directions. The attendant, Mordecai (Tim DeZarn), is old, unfriendly, and more than a little bit crazy. He tells them that they will have no problem getting to the cabin, it's the getting back they should be worried about. The kids laugh at him, he becomes sarcastic and aggressive, and there's almost a fight when he refers to Jules as a whore. Instead, everyone gets back into the RV and they drive away. They have to go through a u-shaped tunnel in the mountain to get to the cabin. As they pass through it, a bird tries to fly across the ravine and hits an invisible shield. It electrocutes the bird and it falls, presumably, to its death.
Meanwhile, back at the facility, the phone rings and Hadley answers. It's Mordecai. He reports that the college kids are on their way to the cabin and tells them how the reveler almost messed it up for them and they should be careful. Then he gets mad because Hadley has put him on speakerphone; he hangs up while Hadley and Sitterson laugh.
They arrive at the cabin and unpack. It's obvious that they are still being watched by cameras set up by the facility people. Holden is in his bedroom putting on his bathing suit when he notices an awful painting on the wall. He takes it down and underneath it there's a window into the next room where Dana is staying. She starts to take off her clothes, unaware that the mirror in her room is revealing everything to Holden in the next room. Holden runs into Dana's room and tells her what's going on and they switch rooms. Now Dana can see Holden and she definitely likes what she sees.
All the people at the facility have gathered to place bets on what fate the people in the cabin will choose. Hadley really wants it to be the merman. A new agent called Truman (Brian White) is shocked by the way he sees the others behaving. A more seasoned agent, Lin (Amy Acker), tells him that she understands how he feels, but he shouldn't judge the others for their seemingly flippant behavior. Truman, however, continues to question Hadley and Sitterson about the proceedings; Truman thinks it's unfair, although they all seem to understand that what is going on is of the utmost importance.
At the cabin, everyone goes into the living room and starts drinking. Marty continues to smoke the pot he brought. They're all getting pretty tanked and start to play Truth or Dare. Jules is dared to make out with a wolf head mounted on the wall. Then it's Dana's turn. She has just chosen dare when the door to the basement flies open, startling them all. They dare her to go down into the basement. She does and the rest of them follow. There is a ton of really strange stuff down there. Dana picks up a diary. Curt chooses a puzzle ball and tries to open it. Jules likes a wedding dress and starts to put on the necklace that goes with it. Marty is looking at a conch shell and Holden is mesmerized by a child's jewelry box that opens to reveal a dancing ballerina when, all of a sudden...
...the people at the facility are quiet and on the edge of their seats...
...Dana says "Hey guys! Listen to this." Everyone else puts down what they were looking at and walks over to her. The diary belonged to a young girl who was brutally beaten by her father. There is something about how they will all return once someone reads some Latin words at the end of the diary. Marty says they shouldn't read it. He hears a voice tell Dana to read it. No one else seems to hear it. Against the advice of Marty, Dana reads the Latin and somewhere outside, the family from the diary returns from their graves all zombie-fied.
At the facility, it turns out that maintenance and the new intern have won the pool with their selection of Redneck Zombies. Hadley is really bummed he won't get to see a merman.
At the cabin, the kids go back to the living room. Jules and Curt are acting out of character. Jules is dancing very suggestively in front of the fire, Curt is being aggressive and insulting about his girlfriend. Marty notices this but his concerns are brushed off by the others. Curt and Jules decide to go for a walk. Thanks to some pheromone fog, they start to have sex in the woods but they are stopped by the zombies. Jules is stabbed in the hand but Curt saves her. He is stabbed in the shoulder but survives. Jules is recaptured and beheaded while Curt watches. He gets away and runs back to the cabin.
As Jules dies, Hadley and Sitterson recite what seems to be a prayer. Hadley pulls a lever and blood runs into a grooved stone tablet that contains the outline of a female figure: the whore. The ground starts to shake.
Marty hears a voice in his head and goes outside to see Curt running towards him, fighting off a zombie. They both run inside and lock the door. Curt tells everyone that Jules is dead. They decide to barricade the house and stick together. Courtesy of the facility, a voice tells them to split up but only Marty consciously hears it. He begs the others not to split up but no one listens and Dana, Holden and Marty each go into their own rooms. The doors promptly lock behind them.
No one at the facility can figure out why their tricks aren't working on Marty. He's not following the plan and he can hear the voices. They're worried he's going to ruin everything. In Marty's room, he gets startled and breaks a lamp. He picks it up and finds a camera. This is proving everything he's been saying about this place. He's about to investigate further when a zombie comes through the window and pulls him outside. They struggle. Marty is stabbed in the back and dragged out of sight. Bad noises follow. Poor Marty.
People at the facility are relieved that Marty won't be ruining their plan. However, they're still investigating to see why their drugs didn't work on him. They determine that when they were lacing his pot with their drugs, they missed one of his stashes and what he was smoking was making him immune to their tricks. Blood runs into the outline of the reveler. The ground shakes.
A zombie tries to break through Dana's window. Hearing this in the next room, Holden breaks the glass between their rooms and pulls her into his. They find a door in the floor that leads to another room in the basement. It appears that this is the room where the father beat and tortured the girl from the diary. They try to find a way out but the door won't open. Just then, one of the zombies finds them and stabs Holden in the back. Dana stabs the zombie repeatedly just as Curt opens the door from the other side.
The three of them get in the RV. The door closes and a bloody hand print is seen on the outside of it.
As they head toward the tunnel, Hadley realizes that the demolition crew never set off the explosion that causes the tunnel to cave in and block their exit. As the trio frantically tries to get away, Hadley and Sitterson are just as frantically trying to correct this oversight.
The RV makes it halfway through the tunnel when it starts to cave in. They reverse back the way they came and make it out just in time. Curt has a dirt bike in the back of the RV and he decides to jump the ravine and go get help. Like the bird, he hits the invisible barrier and dies. (Blood runs into the outline of the jock.)
Dana and Holden see what happened to Curt and realize that Marty was right all along. They head back towards the cabin trying to figure a way out. Holden is stabbed through the head (blood fills the outline of the scholar) and the RV crashes into the lake. Turns out there was a zombie in the RV. Dana fights off the zombie, gets out through the overhead hatch, and swims to the surface. She makes it onto the pier when the zombie comes up from the water and starts beating the crap out of her.
Back at the facility, they are celebrating a successful night. Evidently, the "virgin" doesn't have to die for the plan to be successful. This is extremely important since all of the other sites (Japan, Germany, etc.) have failed to complete the ritual. They open a bottle of champagne and start drinking. The red phone rings. Hadley answers. A tense conversation follows. Apparently, the rules weren't followed. One of the others is still alive. If Dana dies first, they will lose.
Dana is still getting the crap kicked out of her by the zombie dad. Marty comes out of nowhere and beats the zombie with his giant bong until he falls into the water. He grabs Dana and they run into the woods. The zombies are after them. He jumps into one of the graves the zombies came out of and starts digging. Dana can't figure out what's going on. Suddenly, Marty opens a door and they fall into a room right before the zombies grab them.
Marty tells Dana that this was all set up. He's discovered an access panel and started playing with the wires inside; this is why the tunnel never exploded when it was supposed to. Marty shows Dana an elevator and deduces that someone sent the zombies to attack them. She's not sure about getting in the elevator, but they don't have any other options. Through the glass window of their elevator, Dana and Marty can see many other elevators that contain supernatural creatures connected to the strange items in the basement of the cabin. The Sugar Plum Fairy, the Puzzle Ball, the doll faces, the killer bride, etc.. Dana recognizes the connection and deduces that the group "chose" the means of their own deaths, meaning the zombies.
Meanwhile, the observers are in an uproar because Dana and Marty have penetrated their facility. They make plans to kill Marty in order to preserve the intended order of sacrificial deaths. Pinpointing the elevator number, an armed guard is sent to them and instructed to kill both of them, Marty first, but he fails when a zombie corpse in the elevator distracts him. Dana and Marty kill him and move out into the hallway. A female voice speaks to them over a PA system, sympathizing with them for their predicament, but insisting that Dana and Marty must die. More armed guards show up and start firing on them, and they run into what looks like a control room and hide. Dana realizes that there is a control panel that monitors access to the elevators containing the monsters. As they are being attacked by soldiers with machine guns and other artillery, they randomly start to push buttons; Dana finds a large one that says "PURGE SYSTEM," and suddenly alarms start going off all over the facility. The guards all pause in terror, then all of the elevators open while monster after monster emerges. The soldiers are massacred and the monsters get into all areas of the facility, slaughtering the workers. Marty and Dana are cornered by monsters, but they climb through a hole where one of the walls was smashed in during the carnage.
In the facility's control room, Hadley, Lin, and Truman are killed by monsters. Hadley finally gets to see his merman right before it kills him. Sitterson manages to activate an escape hatch and emerges into a stone hallway, but he is fatally stabbed by Dana; this is where Dana and Marty have ended up as well. Before Sitterson dies, he tells Dana, "Kill him." Dana is afraid to go on, but Marty gives her a gun he took from a dead guard.
Marty and Dana end up in the room with all the character outlines. Dana realizes that there are five stone tablets, one for each of them--Dana, Marty, Holden, Curt, and Jules. Everything that's happened to them has been part of a ritual sacrifice. The Director (Sigourney Weaver) appears; they recognize her voice as the one that spoke to them over the PA system. She explains about the facility and their purpose. She says the ritual is older than anything known to man; even she and her peers aren't sure of everything, but the ritual is conducted worldwide in order to appease "the Dark Gods" who once ruled the Earth. She says the monsters they've seen are nothing compared to them, and both Dana and Marty realize they are standing over a pit that leads to where the old Gods are sleeping.
The Director explains that the ritual is meant to keep them dormant, and must follow specific rules. There are five sacrificial victims. The whore (Jules) dies first, and after that, four more archetypes: the scholar, the athlete, the fool (a.k.a the reveler), and the virgin. The order of their deaths doesn't matter as long as the whore is first to die and the virgin is the last one alive. The Director says it is up to the Gods whether the virgin (Dana) lives.
If the sacrifice is not completed, the old Gods will come to the surface and destroy mankind. The Director says Marty must die to save the world. Marty says that if a bloodthirsty ritual is required to save mankind, then maybe mankind isn't worth saving. Marty is hurt when Dana raises the gun to kill him; she is conflicted, but she doesn't want the world to end. Without warning, Dana is attacked by a werewolf, which proceeds to viciously maul her. When she drops the gun, Marty picks it up and fires on the werewolf, and it runs off, wounded. The Director tries to kill Marty, but the zombie girl from the diary appears and kills the Director instead. Marty kicks them both into the pit with the Gods. Dana and Marty make up and smoke a joint while they contemplate the end of the world. The ground shakes and starts to crack open.
The cabin in the woods starts shaking. A giant hand comes crashing up through it and slams down on the ground in front of it as the first of the old Gods reaches the surface.