In the town of Prosperity, Arizona, Sam Parker (KARI WUHRER) is the local sheriff who's trying to raise her two kids - teen rebel Ashley (SCARLETT JOHANSSON) and her younger brother and spider freak Mike (SCOTT TERRA) - by herself while maintaining the law with Deputy Pete Willis (RICK OVERTON).
She isn't happy that Ashley's dating Bret (MATT CZUCHRY), the motorbike riding son of the town's mayor, Wade (LEON RIPPY). The resident of Prosperity - including conspiracy minded radio broadcaster Harlan Griffith (DOUG E. DOUG) -- aren't happy with Wade since the town and its various failed projects - such as the huge indoor shopping mall - have not resulted in what its name suggests.
Wade's latest get rich quick schemes aren't going over that well either. The first involves getting everyone to sell their property to a buyer who has plans for their land, but many are against that including Chris McCormick (DAVID ARQUETTE) who's returned to his hometown. He's inherited his late father's now abandoned mining operations and doesn't want to sell. Rather, his intention is to let Sam know how he really feels about her after a ten-year absence.
Wade's other plan has more disastrous effects. It seems he's been accepting payment for allowing toxic materials to be stored in those mines. When one of the barrels of that waste accidentally falls from a truck en route, it ends up contaminating a nearby pond. A local exotic spider farmer then unknowingly feeds contaminated crickets to his arachnids, resulting in them suddenly and quickly growing to huge sizes.
Once loose, they continue to grow and then threaten the lives of everyone in Prosperity who do what they must to defend themselves and avoid the mutant spiders that eventually overrun their remote town.