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In the town of Ogden Marsh, Iowa, Sherriff David Dutton (Timothy Olyphant), enjoys a baseball game. His deputy, Russell (Joe Anderson), spots a local resident, entering the outfield holding a shotgun. David is forced to shoot and kill the unresponsive local. David and his wife Judy (Radha Mitchell), the community doctor, begin to notice other town residents exhibiting bizarre behavior. The next night, a local farmer burns his house down with his wife and son trapped inside, killing them.
While investigating the discovery of a pilot's body in a swamp, David and Russell discover a cargo plane submerged under the water. Communication services are lost, and that evening soldiers wearing hazmat suits arrive to take all residents to quarantine at the high school. Everyone is examined for symptoms of infection. Judy does not pass the examination as a result of a fever brought on by her pregnancy and is separated from David. She tries to explain but is sedated anyway. She wakes strapped to a gurney as the perimeter of the facility is breached by the infected. The military personnel evacuate, leaving Judy and others behind. David is nearing evacuation, but escapes and rejoins Russell in town on a mission to save his wife. They rescue Judy and her medical assistant, Becca (Daniele Panabaker) from an infected citizen whom is killing those in the infirmary with a pitchfork.
While investigating the discovery of a pilot's body in a swamp, David and Russell discover a cargo plane submerged under the water. Communication services are lost, and that evening soldiers wearing hazmat suits arrive to take all residents to quarantine at the high school. Everyone is examined for symptoms of infection. Judy does not pass the examination as a result of a fever brought on by her pregnancy and is separated from David. She tries to explain but is sedated anyway. She wakes strapped to a gurney as the perimeter of the facility is breached by the infected. The military personnel evacuate, leaving Judy and others behind. David is nearing evacuation, but escapes and rejoins Russell in town on a mission to save his wife. They rescue Judy and her medical assistant, Becca (Daniele Panabaker) from an infected citizen whom is killing those in the infirmary with a pitchfork.
Now they know they need to get out of town. Unable to locate a working vehicle they head out on foot. They encounter Becca's boyfriend, Scotty, when they pass through his farm. Soldiers raid the farm, shooting Scotty and his mother, and burn the bodies. The group repairs a patrol car the sheriff has hidden in his garage, and before getting on the road find themselves facing the family of the resident he shoot on the field. Once on the road they are spotted by an attack helicopter. In an attempt to hide they drive into a car wash for cover only to discover it is operated by infected employees who attack them and pull Becca from the car. Racing to try to rescue her as she is hung from the garage they temporarily abandon the car none to soon as the helicopter destroys the car in a precision military strike.
Now on foot they disable a passing government SUV with a police spike strip. The Driver a government agent reveals the cargo of the downed plane contained a biological weapon being sent to Texas to be destroyed is designed to de-stabilize the population. Russell shoots the agent and is confronted by David and Judy about his increasingly erratic behavior.
Russell realizes he is infected and after being disarmed, begs to go on with Judy and David, later dying while distracting soldiers at a road blockade, so Judy and David can sneak past.
By nightfall David and Judy arrive at the truck stop where the uninfected residents were evacuated too, only to find it not only abandoned but that everyone was burned to death. They discover a government radio in the debris left behind. Suddenly they realize they are being hunted by three infected people and only narrowly managed to escape in a semitruck. As they drive away from town they hear the countdown on the radio. As the countdown reaches 0 the town of Ogden March is eradicated by a nuclear explosion which flips their truck.
Back on foot the couple head towards the next big town or Cedar Rapids. As the couple walk towards Cedar Rapids, a view from a military satellite highlights the city, and the words "initiate containment protocol" appear, signifying another containment attempt since David and Judy are unknowngly infected by the virus.
In the closing credits, a news clip from Cedar Rapids Channel 9 is shown in which the newscaster reports that a huge explosion originating from the Dakon Petrol chemical plant started a massive fire in Ogden Marsh, "with eyewitness reports of a 400-foot fireball that lit up the sky." He goes on to report a second explosion at a nearby truck fueling station, alluding to the truck stop. He says a perimeter has been set and civilians are not being allowed into the area. After that, the news clip cuts to a soldier with his rifle brandished, then to a snarling crazy, and finally simply the words "Signal Lost," strongly implying that the much larger city of Cedar Rapids was infected after the events of the film.
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