Oasis Plaines, Oklahoma
At a construction site for new suburban upscale homes, one of the workers notices ground tremors and when he feels the ground, he falls through a sinkhole. The worker, Dustin, breaks his ankle and when his friend Travis goes for a rope, Dustin sees thousands of bugs which begin to cover him. When Travis comes back, Dustin is dead.
The brothers are at a bar and Dean is raising money by hustling pool when Sam spots a newspaper article about a worker dying of mad cow disease. Sam realizes the guy, Dustin, died far too quickly and thinks something is up. They pretend to be Dustin's nephews and talk to Travis, who tells them what he saw and points them to where it happened. Sam goes down into the hole and finds some beetles, but no tunnels or tracks. Dean spots a realtor's BBQ and they go in and meet with the realtor, Larry Pike, while claiming to be looking for a house for their father.
While seeing the house they notice Larry's son, Matt, is big on bugs and Sam meets with him over a pet spider he's using for a practical joke, while Dean learns a surveyor died a year earlier from an allergic reaction to bee stings. Dean thinks the son might be involved and then they break into an empty house to stay the night. Larry's sales manager, Lynda, is at home taking a shower when spiders swarm out of the shower head and she panics and falls through the shower glass, then dies covered in bugs.
The next morning Sam picks up the call on the radio scanner, and they go to the house. Larry is there to identify the body. They sneak into the house and find the spiders, and connect it to Larry's son. They catch up to him getting off the school bus and follow him into the woods where he's observing a praying mantis. They confront him and Matt reveals something is going on with the bugs but his dad won't listen to him. He takes them deeper into the woods where the insects are congregating, and find a worm-covered mound with a skull inside.
They find more skeletons in what is clearly an unmarked grave, and go to the local college for an appointment while discussing their issues about how their father wasn't happy with Sam and his life choices. Dean reveals their father used to check up on Sam without his knowledge. They meet with an anthropology professor and have him look at the bones – he reveals there weren't any records of graveyards but local Indians were often relocated. The professor directs them to a nearby tribe and a Joe Whitetree, who immediately spots they're not students. He reveals that the cavalry raided their village and on the sixth day the chief laid a curse that no white man would come on their land and nature would rise up against them. Further, that on the night of sixth day, none would survive.
They figure when the deaths first occurred, at the spring equinox, and that that night is the sixth night. They head back to get Larry and his family out While at his house, Matt notices a hole in the backyard and cockroaches start to pour out.
Dean tries to fool Larry into believing there's a gas leak but he isn't fooled, so they call Matt. Dean tells him to lie and fake some pains so his parents will take him to the hospital. The brothers get there and the family is still there- Matt told him the truth and he thinks they're nuts. Before they can convince him, they hear the sound of a huge swarm of bugs and then see them heading for the house. They get into the house for refuge and start to seal the place up. They have no choice but to wait it out, as the curse is supposed to end at sunrise.
Dean grabs a can of bug spray as the bugs start to come in through the fireplace flue – it bursts open as the bugs swarm in and Dean improvises a flamethrower out of the spray can. They take refuge in the attic but the termites start chewing through the wood then bees pour through the resulting hole. They manage to seal it up with a board and brace it, but the termites create another hole and then break through the first one. All looks hopeless but just in time the sunrises and the bugs swarm out through the hole, going back to wherever they came from.
Later the brothers meet with Larry who announces the development project has been put on hold, and who will make sure no one lives there again. But Larry and Matt have bonded, much to Sam's satisfaction. Matt is dumping his bug collection into the trash. Sam resolves to find their father so he can apologize.