The owners of the Three Feathers Indian Casino have acquired the town of South Park. The citizens are being forced off their land to make way for a new super highway. Faced with saying goodbye to their friends and their way of life, the boys rally the townspeople to fight back against the rich and powerful Indians.
The boys and their parents go to a casino in a Native American reservation, where Gerald ends up losing the house betting on blackjack (but tries to make it look as if it is his son Kyle's fault after he stated he wanted to leave the casino by making it sound like he wanted to leave South Park). It turns out he's not the only one. The entire town is bought out by the Native Americans, who plan to tear it down so that they can build a superhighway connecting their casino to Denver, Colorado. The entire town is forced to leave their homes, and have no way to buy back their town.
The boys meet with some of the other kids in town to come up with an idea. An unfamiliar, "new boy" called Alex points out that they have to save the town. The boys advise their parents to get all the money they have, and then go bet it at the casino. If they win a round of roulette betting $10,000 on a single number, they would have enough money to buy back the town, plus $50,000. Amazingly, they win, but then, as expected from avid gamblers, the adults bet all their winnings again, and lose. On the drive to town Randy doesn't understand Stan's anger at the town betting the money, saying that, "you don't quit when you're on a hot streak." He even grows angry when Stan correctly says that Randy and the rest of the town got greedy, which Randy venomously denies.
When they are selling their homes, Stan, Kyle,Cartman, and Kenny try to get them to stand up for the town and are backed up by Alex ("They don't own our town, we do.") and save South Park. At first the adults, being plain stupid as usual, say they will move to Middle Park instead. The boys testify "until the Native Americans come to take Middle Park too." While the adults remain naive, the 4 run outside to stand in front of the Native Americans' bulldozers, blocking their path. Before he leaves, Cartman shouts at them, "You're all a bunch of goddamn pussies!" shocking the townsfolk. They soon join the boys in blocking the path. Alex rejoices with the rest of the townspeople. The casino's owner, Chief Runs With Premise, plots another way to get rid of the townspeople.
He decides to give them all blankets, after infecting them with S.A.R.S. using naked Chinese men; the whole town gets sick, except for Stan Marsh, and his father tells him that if he doesn't find a way to cure SARS, only 98% of the town would be left. At the same time, however, the casino owner's son, Premise Running Thin, gets infected with S.A.R.S. accidentally, and none of the Native Americans' herbs are able to cure him. The owner decides to take out his anger on the townspeople with Operation Shock and Awe. Meanwhile, Stan goes to a wise old man in a trailer in another town, who gives him an "inward journey" brought on by sniffing paint thinner. He discovers the middle-class white man's way to cure sickness by utilizing Campbell's chicken noodle soup, DayQuil, and Sprite. The people of South Park all recover.
The casino chief, Runs With Premise, arrives and is shocked to find the people are healthy and not half-dead. He begs them for the cure to S.A.R.S. for his son, and they give it in exchange for their town back. Alex gives the lesson that the South Park is really more than a town, it's a community of people. Stan finally asks who he is, and Alex explains that he's some guy named Alex Glick who got to do a guest voice. Kyle tells him to "get the hell out", and Alex leaves, waving to the home TV audience, sending a greeting to his family.