Four American tourists--Eric, his girlfriend Stacy, her best friend Amy, and Amy's boyfriend Jeff--are vacationing in Mexico. They befriend a German tourist named Mathias and a trio of hard-drinking Greeks who go by the Spanish nicknames Pablo, Juan, and Don Quixote. Mathias discovers that his brother Heinrich has followed a woman to an archaeological dig and asks the foursome to come with him to bring Heinrich back, saying it will be only a day trip. Pablo decides to tag along, though he speaks neither English nor German: he leaves a note and a map for the other two Greeks, telling them to come along when they sober up, and brings three bottles of tequila for the trip. The six get a bus to a small town and then hire a cab to take them to the ruins. The cab driver tries to dissuade them but they go anyway.
After thrashing through the jungle for a couple of hours following the map that Heinrich has left, they find a small Mayan village. The villagers ignore them completely, but a boy follows them. Backtracking, they find a path through the jungle which has been carefully camouflaged. Breaking through the palm fronds, they find a trail leading up to a hill. The hill is covered with flowering vines and is ringed by blackened earth with white crystals scattered throughout it. The boy rides back towards the village on his bike. As they approach the hill, armed villagers on horseback arrive (alerted by the boy) and try to keep the tourists from climbing the hill. Amy, trying to take a picture, steps backwards over the blackened earth and onto the vine-covered hill. The villager with the gun (the others have bows and arrows) then forces all six across the blackened gap and onto the hillside.
They start up the hill in search of the archaeological dig and find only a couple of tents. They can see that more and more villagers, all armed, are arriving and setting up camps around the base of the hill. They walk down the hill and discover nestled among the vines a human body: Heinrich, shot to death with three arrows and partially decomposed. The villagers keep their weapons trained on the tourists until they walk back up the hill.
They realize that the vines contain an acidic sap that has burned their hands after they pulled the vines away from Heinrich's body. Exploring the hilltop, they find a mine with a windlass on top of it: vines have grown around the rope leading into the mineshaft. Suddenly they hear the sound of a cell phone ringing from the bottom of the mine shaft. They carefully pull away the vines from the rope and prepare to send someone down to retrieve the phone: Pablo volunteers by knotting the rope around himself. They send him down the well along with a lantern they found in the tent, but when he's halfway down, the vine tendrils that remained on the windlass leak more acid and burn through the rope, sending Pablo plummeting to the bottom, where he begins to scream and doesn't stop.
Jeff and Mathias cut the burnt sections from the rope and knot the rest together, then send Eric down the well to rescue Pablo and get the cell phone. The rope is twenty feet too short, so Eric jumps, landing on Pablo and on the shattered lantern, which cuts his knee severely. He shouts that Pablo has broken his back, so Jeff and Mathias make a backboard out of aluminum flagpoles and fashion a rope out of pieces of one of the tents, and then send Amy down so she and Eric can put Pablo on the backboard.
That night, Jeff heads down the hill to see if there's any way they can slip past the villagers, but as he nears the bottom, birds begin screeching, and he realizes he won't be able to get by: there are too many of the villagers, and they're determined not to let anyone off the hill. He returns to the top, where Pablo is in a bad way. Some of them try to sleep.
The next morning, Jeff returns to the bottom of the hill to post signs warning anyone who comes to the trail not to enter. He realizes that there are no flies on the bodies, no birds: no living things on the hill at all except the tourists and the vine. He finds more skeletons and discovers that they've all been picked completely clean of flesh, apparently by the vine. He discovers that someone has tried to make a warning sign by carving "DANGER" into the bottom of a metal baking pan, but the pan was buried among the vines. He goes back to his own signs and finds that the metal poles have been torn down by the vines, the paper of the signs dissolved by the acid.
Eric wakes up to discover that a vine has wrapped around his legs and inserted itself into the wound on his knee. Amy is so horrified that she goes outside to throw up, and then watches as a tendril of the vine snakes along the ground to the vomit and sucks it up. Inside the tent, using the only knife they have, Mathias cuts the vine out of Eric's leg and then stitches up the wound. Eric grows increasingly paranoid, believing that the vine is still growing inside him, in his leg and even in his chest.
Jeff tells the others that the vine has eaten every living thing that ever lands on the hill, that the Mayans have burned and salted the earth around the vine to keep it from spreading, and that they're being held on the hill because if they leave, they'll carry back spores which will spread the vine. Already, tiny, fuzzy tendrils have begun growing on the clothing and every other organic thing the tourist brought to the hill with them, slowly dissolving their clothing. Amy refuses to believe they're trapped, saying the Greeks will come and save them. Jeff insists they ration their food and water in case they're on the hill for more than another day.
Pablo's legs become gangrenous. Jeff and Mathias decide the only way to save him is to cut them off below the knees, rationalizing that he won't feel anything because he's paralyzed from the waist down. He's conscious for the whole operation. They sterilize the knife with fire and tequila, break the bones with a rock, cut the legs off below the knees, and cauterize the wounds with the baking pan heated in the fire.
Jeff decides he and Amy should go back into the mine to find the cell phone, which they still hear ringing from time to time. They reach the bottom and head down a shaft, following the sound of the phone, when Jeff senses that if they go any farther they'll fall down a pit, which the lantern shows to be the case. Jeff finally realizes that the vine has been making the cell-phone sound to lure people to their doom, and also made the bird sounds which alerted the villagers when he tried to leave the hill: it can reproduce every sound that's ever been made on the hill. They struggle to leave the mine, and succeed, but they hear a sound which they realize is the vines laughing at them. Everyone else hears the sound of laughter as well: all the vines all over the hill are mocking them.
The tourists take turns keeping watch at the bottom of the hill in case the Greeks come. While left alone, Eric tries to cut into his chest to remove more of the vine he believes is in him, but Jeff manages to stop him before he can do too much damage. While Jeff is at the bottom of the hill and Mathias is sleeping, Amy, Eric and Stacy get drunk. They try to keep one another in good spirits, but the drunken banter eventually turns nasty. Suddenly, the vine begins loudly repeating all the terrible things they've said about one another and about Jeff and Mathias.
A rainstorm moves in that night, and they collect drinking water. Jeff and Amy have a fight; Amy begins vomiting, but Jeff refuses to go to her, even after she calls out his name and seems to vomit some more. She falls asleep a short distance from the tent. Mathias discovers that she wasn't vomiting the second time: the vine pushed itself down her throat and suffocated her. Jeff tries to revive her with CPR but she's dead.
Eric wakes up after sleeping and discovers that the vine has pushed its way back into his leg wound and also the new one on his chest, much worse than the first time. The vines are moving around inside him. Mathias cuts them out, but Eric, increasingly paranoid, believes that they're still inside and will eventually kill him.
The next morning, the vine sends out the smells of food to torment the survivors. Jeff proposes that the thing isn't even a plant, but just looks like one; it doesn't seem to have any roots. He tries to get the others to understand that even though they have water, they could be on the hill for a long time, and they'll die without food, so they should consider eating Amy's body. The others refuse, so they wrap the body in a sleeping bag and plan to bury it that night when it's cooler.
Everyone hears Amy's voice calling Jeff's name and begging for help: they see the sleeping bag moving, but when they open it, they find it's full of thrashing vines which have devoured Amy.
A huge rainstorm strikes. Jeff heads to the bottom of the hill to see if he can escape, concealed by the heavy rain. Stacy and Mathias are outside the tent under a lean-to; Eric is alone in the tent. He can hear the vines mimicking Stacy and Mathias' voices having sex, and he angrily asks Stacy if it's true. While they're fighting, the vine kills Pablo by suffocating him.
Jeff runs for it but it struck down by three Mayan arrows. The vines grab him and pull him into the undergrowth, where they suffocate him. The tendrils pass Jeff's hat up the hill and set it on Pablo's skull, then imitate Pablo's breathing to draw the others out to show them what's happened to Jeff.
Eric's in much worse shape. Stacy and Mathias go down the hill to see if Jeff really is dead. Eric, left alone, gets the knife and begins to cut himself open to get out every bit of the vine. He shreds nearly all the skin off his body and cuts off one of his ears. The vines mockingly tell Stacy and Mathias that Eric is dead: they rush up the hill where they find him in tatters and bleeding badly. Mathias tries to stop him but Eric stabs Mathias to death to keep him from getting the knife. The vines grab Mathias's body and pull it into the undergrowth. Stacy tries to comfort Eric; he begs her to kill him. She pulls the knife from Mathias' chest and gives it to Eric, but again he begs her, saying he's too weak to do it himself. She stabs him to death.
Stacy realizes she can't stay on the hill alone for another night. After eating all the remaining food, she walks down the hill with the knife. She realizes she should have cut the rope on the windlass leading down into the mine, but can't bring herself to go back up. She sits on the trail, staring at the Mayans, and cuts her wrists, thinking that her bones will warn the Greeks that they shouldn't go any farther. As she bleeds to death, the vines pull her off the trail and into the undergrowth: she's too weak to resist, and the vines suffocate her.
The next day, the other two Greeks, with some Brazilian tourists in tow, find the trail. A little girl--who's acting as a sentinel, as the little boy on the bike was--runs back to the village, but the new tourists are already halfway up the hill, calling for Pablo, before the men on horseback arrive.