In the town of Ogden Marsh, Iowa, David (Timothy Olyphant), the local sheriff enjoys a baseball game. His deputy, Russell Clank (Joe Anderson), spots Rory Hamill, a local resident, entering the outfield holding a shotgun. David is forced to shoot and kill the unresponsive Rory. David and his wife Judy (Radha Mitchell), the community doctor, begin to notice other town residents exhibiting bizarre behavior, including listlessness and repetitive speech. 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 military aircraft submerged under the water. Soon after, communication services are lost in town, and soldiers arrive to take all residents to quarantine at the high school. Everyone is examined for symptoms of infection. Judy does not pass the examination and is separated from David. She explains her fever is due to pregnancy, but is sedated anyway. She wakes strapped to a gurney as the perimeter of the facility is breached by the infected townspeople in an effort to escape. The military personnel evacuate, abandoning Judy and the other civilians. David is nearing evacuation, but escapes and rejoins Russell. They rescue Judy and her hospital assistant, Becca (Danielle Panabaker).David, Judy, Russell, and Becca make their way out of town on foot, unable to find a working vehicle. They encounter Becca's boyfriend, Scotty, when they pass through his farm. Soldiers raid the farm, shoot Scotty and his mother, and burn the bodies. They learn that the soldiers have been ordered to shoot all civilians who have potentially been exposed. The group repair a patrol car, and, once on the road, are spotted by an attack helicopter and drive into a car wash for cover. The infected attack and kill Becca by hanging her from the ceiling with a car wash hose, and the helicopter destroys the car. On foot, Russell disables a passing government SUV with a police spike strip. The driver, a U.S. government intelligence officer, reveals the cargo plane contained "Trixie," a "Rhabdoviridae prototype" biological weapon. Enraged, Russell shoots the driver and threatens Judy and David. When confronted about his behavior, Russell realizes he is infected and, after being disarmed, begs to go on with Judy and David. He later dies while distracting soldiers at a blockade, so that Judy and David can sneak past.
David and Judy arrive at a truck stop to search for a vehicle, discovering the military also executed those who were evacuated. Fending off the infected, they escape in a semitruck. Ogden Marsh is destroyed in a massive explosion as they flee, and their truck flips in the passing shockwave. As the couple walk towards Cedar Rapids, a view from a military satellite highlights first the couple, then the city, and the words "Initiate containment protocol" appear, signifying a new containment attempt.
In the credits, a news clip is shown in which the newscaster Bruce Aune of KCRG-TV 9 News reports that an explosion originating from the Dakon Pendrill 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 then cuts out completely as the signal is lost.
The following gallery are the international Blu-ray covers of The Crazies: