Ten years after graduating high school, three friends, Jerry (Matthew Lillard), Dan (Seth Green) and Tom (Dax Shepard), find out that their childhood friend, Billy (Antony Starr), died in a para-sailing accident in Costa Rica. After the burial, they take a trip down to memory lane and enter their tree house, where the four hung out when they were children. They find a map leading to D. B. Cooper's lost treasure that Billy has apparently been working on his whole life. Dan takes a break from his job as a doctor and joins Jerry and Tom on a camping trip to find the treasure.
They take a canoe down the river and find Grandpa's Nose (a rock formation), and they stay on the riverside for the night. Standing around the camp fire, they discover they forgot to bring food; so Tom goes out to catch some fish. Despite his shining skills, a grizzly bear shows up and chases the group away. Dan trips and is caught up with by the bear, who thinks Dan is its cub. It brings Dan back to its 'nest' and forces him to eat a mutilated dead squirrel. Dan manages to escape and the trio ends up sleeping in a tree. In the morning, they find all their gear ripped up and completely destroyed by the bear - even Dan's cellphone, which the animal swallowed. The bear, they find to their dismay, had also ripped a hole in the map.
The trio takes off in the river, but, unable to read the map, they go the wrong way. The split leads them into rapids where they are nearly killed and drowned. The map is lost, and they end up falling off a waterfall, but landing safely in a belly of water. Unfortunately, their canoe has been smashed to pieces. They take off into the woods with a compass and find themselves at a pot farm, in which two violent farmers, Dennis (Abraham Benrubi) and Elwood (Ethan Suplee), mistake them for thieves and start shooting at them. The friends escape into the farm, but the security flares go off and hit the growth, causing a bunch of smoke to wallow around and get the trio effectively stoned. While the farmers, wearing bandannas over their faces, are on their tail, the guys fall into a pond barely escape, using reeds to breathe. The farmers take off, and the guys then run into the woods. In the morning, the farmers find their crop burned and they set off to kill Jerry, Dan and Tom.
The trio meets two hippie girls far into the forest, who treat the men with food, communication, and love up in their huge tree. Using the radio, the farmers find them and attempt to cut down the tree, both distressing and enraging the hippie girls. They drop paper bags full of feces at the farmers to distract them while the guys escape. Half naked, the guys are lost into the woods, while it is pouring rain. The only way they have to survive is to hold on to each other for warmth. Suddenly, they are caught by a man living up in the mountains, who takes the them up to his hut and provides them with clothes. The man is named Del Knox (Burt Reynolds), once D. B.'s partner before his death.
The next morning, the farmers find them and assault the house. The guys escape while Del Knox shoots at the two bad guys with his revolver. The guys stumble upon the site in which D. B. crashed landed, discovering his corpse along with the suitcase holding the money. It turns out that D. B. burned his share of the money, just for a few more minutes of life. They then toss their valuable possessions on his body, including Dan's C-3PO action figure, Jerry's Brian Bosworth card, and Tom's condom. The only way out of the cave is for Dan to crawl through a small tunnel. The farmers find Jerry and Tom below and Dan comes from the ground and hits them with a log. The farmers fall down and they engage in a brawl with Tom and Jerry, consisting of Tom kicking the gun out of Elwood's hands, Dennis tossing Jerry onto the ground, Then Tom leaps onto Dennis's back so Dennis spins Tom off, then they begin punching, kicking and biting. Eventually, a sheriff (who actually helped Dan, Tom, and Jerry in the beginning) arrives; however, it is discovered that he was working with the pot farmers all along. The three are cornered and Jerry, who took one of the farmer's grenades, flips off the pin but accidentally drops it. Moments before it blows, he throws it towards the bad guys; it explodes, causing a tree to fall on the farmers and sheriff. The three bad guys are arrested afterwards.
In the end, Jerry, Dan, and Tom earn half of the remaining money from D. B. Cooper's partner. Jerry proposes to his girlfriend, Dan starts a relationship with one of the hippie girls and gets laid for the first time, and Tom is a camp counselor for a children's summer camp, who ends up telling his troop all about the camping trip.