The film begins with a reenactment of the gruesome act of cannibalism described by the prosecuting attorney during Alferd Packer's 1883 trial. During this sensationalized account, a haggard Packer (played by Trey Parker) repeatedly insists that was not how it happened. During a break in the trial, Packer is enticed by journalist Polly Pry to tell his side of the story, which he proceeds to do, via flashback. He opens his tale with better times, galloping freely over green fields on his trusty horse Liane, singing to her ("Shpadoinkle").
In 1873, Packer was part of a group of miners in Bingham Canyon, Utah who hear of new prospects in Breckenridge. Together, the small group decide to travel together into Colorado Territory to stake a claim. The journey gets off on the wrong foot the original guide, Lucky Larry, dies from a lightning strike, Packer is nominated as the replacement since he claimed knowledge of the area ("Shpadoinkle [Reprise]"). He and Liane set off on what Packer estimates will be a three-week journey with a party of five miners: Shannon Wilson Bell, an aspiring Mormon priest; James Humphrey, who was forced by his father to join the party; Frank Miller, a cynical butcher who reluctantly joins their party at the mine; George Noon, a teenager hoping to meet women in Breckenridge; and Israel Swan, an optimist.
Four weeks later, while attempting to visit Provo for supplies they become convinced they are lost. An attempt to ask a local for directions to Provo proves unsuccessful, with the local warning them of impending doom awaiting them in the mountains. Finally arriving at a frontier post in Provo, they run into a group of three fur trappers bound for Saguache; O.D. Loutzenheiser, Preston Nutter, and their diminutive leader, Jean "Frenchy" Cabazon. The trappers despise the miners, whom they contemptuously call "diggers", yet seem to like Packer's Arabian horse, telling Packer that she's a "trapper horse". Making camp, Packer and company reveal their goals for traveling to each other in song ("That's All I'm Asking For"). The next day, Packer wakes up to discover his horse and friend, Liane, is missing. After Bell wounds his leg in a bear trap, the men attempt to cross the Green River near the Utah border. The group asks Packer if there are any other big rivers that they will have to cross to which he replies, "No, just the Colorado." They camp out for the night after their crossing, with Packer singing a heartfelt song about Liane ("When I Was On Top of You"). Eventually, after a disastrous crossing of the Colorado River the Packer party is spotted by two "Nihonjin" Indians (obviously played by Japanese actors and speaking Japanese). They are taken back to the tribe's encampment near Delta where the chief warns them of a winter storm, allowing them to wait it out with the tribe. Packer's party also find the trappers camping out with the tribe, who proceed to brag about their lives in song and argue over the key of said song before a small altercation breaks out over Liane, whose feedbag Packer finds in their possession ("Trapper Song").
The story returns to the present time, where Packer is sentenced to death by hanging, with his execution to occur in Lake City. That night, alone, Polly muses over the case and Packer's testimony, and she reveals her growing affection for him through song ("This Side of Me"). The next day, Polly visits Packer once again in prison, where he continues his story.
The men set out in the wilderness after Packer learns the trappers have already left, persuading them to leave under the guise of there being a break in the storm. The group begins to suspect that Packer is really only interested in following the trappers to find his horse, and Bell's temper begins to shorten as his wound from the bear trap becomes infected and develops gangrene. They soldier on until they encounter a foreboding "Cyclops", a tall mountain man with a wounded, pus-spurting eye, while unwittingly trying to steal one of his sheep for sustenance. The Cyclops recalls how a Union soldier shot out his eye in the Civil War, and becomes enraged when he realizes Packer's men are not "Southern boys" after they cannot finish the lyrics to "Dixie", causing them to flee. They escape and the badly frostbitten Swan tries to cheer everybody up with a song about building a snowman, only for Miller to destroy Swan's snowman with a pickaxe ("Let's Build a Snowman"). They soon run out of food, resorting to eating their shoes as they become lost in the snow-covered Rocky Mountains. Out of frustration, Bell shoots Swan in the head because he does not appreciate his (Swan's) Pollyanna-esque perspective on their predicament ("Let's Build a Snowman [Reprise]"). The men discuss their dire situation that night over the fire, speaking of the cannibalism that the Donner Party had to resort to in California. They decide to consume the body of their dead companion (but "not the butt") as Miller cuts up Swan's body, and only Bell refuses to partake in the cannibalism. Packer then has a ballet-inspired nightmare involving himself, Liane, and Cabazon. After a few more days, the party loses hope, which leads to talk of sacrificing one of their own ("That's All I'm Asking For [Reprise]"). Packer convinces them for one more chance for a scouting trip, but when he returns, Bell has killed the others, claiming they planned to kill and eat him after Packer left. Packer is forced to kill Bell after threatening to turn him in, realizing he has gone insane. He is then forced to cannibalize the others to wait out the rest of the winter.
Arriving in Saguache sometime later, Packer finds Liane, who has taken to Cabazon, upsetting Packer. The sheriff of Saguache, suspicious of Packer arriving without the rest of his party, eventually finds out the fate of the other members and attempts to arrest Packer for cannibalism at a saloon. A bar-fight between Packer and the trappers (and some of the bar patrons, including the Cyclops from earlier) occurs, which Packer wins after brutally attacking Cabazon's groin using fighting techniques he learned from the Nihonjin chief, leaving Cabazon incapacitated with a high-pitched voice. Following this, Packer attempts to flee to Wyoming, only to later be arrested there and brought back to Colorado to await judgment. On the day of Packer's execution in Lake City, the town breaks into song, celebrating Packer's impending death ("Hang the Bastard"). However, he is saved at the last minute by Polly, who arrives on the scene with Liane. Polly reveals that Packer had gotten a stay of execution from the governor stating that he could not be convicted of a state crime since Colorado was not a state at the time of the incident. Meanwhile Cabazon, whose voice is still high pitched and wants revenge against Packer for their fight in Saguache, states the townsfolk came to see bloodshed and tries to trigger the gallows. The Nihonjin chief saves Packer by cutting his rope with a katana before beheading Cabazon, satisfying the crowd's blood-lust. Packer, seeing that Polly brought back Liane, realizes he doesn't need her anymore and chooses Polly (much to the excitement of the chief, who takes off after Liane with his katana), and the two kiss, only to be frightened by a still-alive but badly maimed Bell ("Shpadoinkle [Finale]").
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