A dog from the Congo, infected with a new strain of Ebola, ends up in Amarillo, Texas. Because the daughter (Hannah) of the pet and feed store owner who ordered and received the dog is a cocktail waitress at a popular local bar, she ends up exposing dozens of people to the virus in one night.
Although the outbreak is a natural one, the homeland security team takes charge, to prevent it from spreading. Their job is complicated by the fact that on the night that Hannah infected everyone, she and her ex-convict boyfriend (Shane) leave Amarillo and head to Las Vegas, where they plan to be married.
Shane means to "go straight", but on the pretext of meeting him for a farewell drink and bachelor party, one of his buddies from the county lock-up (Billy) dupes him into becoming part of a robbery, as the getaway driver. As a result, Hannah, Shane and Billy all leave Amarillo together, Shane explaining Billy's presence by saying they are dropping him at his sister's house along the way. When Shane, Billy and Hannah begin to get ill as they travel on back roads (to avoid contact with anyone because of the robbery), the trio all think that they have the flu.
Shane sees a television newscast at a rest stop and realizes that the police are seeking them because they are carriers of Ebola, and not because of the robbery. Determined to make it to Las Vegas, where he can do the right thing by marrying the mother of his child before they all die, he prevents Hannah from finding out by not letting her answer her cell phone or listen to the radio. Eventually, Billy becomes too ill to continue. Shane leaves him in the bathroom of a rest stop and is forced to tell Hannah the truth about what's going on.
She plays along, but Hannah has already retrieved her cell phone and, out of concern for the welfare of her mother and her baby, secretly returned a call that Frankie made when she found the number at the pet and feed store, after the team has tracked the host/dog to that location. As Hannah and Shane get closer and closer to Las Vegas, the Threat Matrix team closes in on them - finally catching up with them only a few miles out of town.
Because Shane is near death, Frankie ignores an incredulous Kilmer and gives in to Hannah's plea to allow her to continue driving toward Las Vegas, so that Shane will die knowing that he did everything possible to give Hannah a husband and his baby a father. Further infections are avoided because the deadly couple only get a few hundred yards before being unable to continue and are finally apprehended.