A virus called Motaba causing a deadly fever is discovered in the African jungle in 1967. To keep the virus a secret, U.S. Army officers Donald McClintock and William Ford destroy the army camp where soldiers were infected.
In 1995, the virus resurfaces in Zaire. Colonel Sam Daniels, a USAMRIID virologist, is sent to investigate. He and his crew—Lieutenant Colonel Casey Schuler and new recruit Major Salt—gather information and return to the United States. Daniels asks his superior, (now) Brigadier General William Ford, to issue an alert but Ford tells Daniels the virus is unlikely to spread.
Betsy, a white-headed capuchin monkey (a host species for the virus), is smuggled into the United States. When James "Jimbo" Scott—an employee of the Biotest animal-holding facility—steals Betsy and brings her to Cedar Creek, California, to sell on the black market, he is infected. Jimbo fails to sell Betsy to Rudy Alvarez, a pet-store owner who wanted a male for a customer. Rudy is also infected, and "Jimbo" releases the female monkey in the woods. He develops symptoms on a flight to Boston and infects his girlfriend, Alice. They are hospitalized, and Dr. Roberta Keough—a CDC scientist and Daniels' ex-wife—investigates their illness. Jimbo, Alice, and Rudy die, but Keough determines that no one else in Boston was infected.
Technicians at a Cedar Creek hospital, including Henry, run tests on Rudy's blood; Henry is infected when he accidentally breaks a vial of Rudy's blood. It is later found that the virus mutated into a strain capable of spreading like influenza, and a number of people are exposed in a movie theater. Daniels learns about the infection and flies to Cedar Creek against Ford's orders, joining Keough's team with Schuler and Salt. As they begin a search for the host animal, the U.S. Army quarantines the town and imposes martial law. Schuler is infected when his suit tears, and Keough accidentally sticks herself with a contaminated needle. Ford provides an experimental serum to treat the sick (which fails because of the mutation), and Daniels realizes that he was aware of the virus before the outbreak. He confronts Ford, who admits that he withheld information to cover the fact that the original Motaba strain was purposefully engineered by the military as a bioweapon; the 1967 outbreak in Africa had in fact been a test-run of the virus, which subsequently infected the local monkey population despite Ford's and McClintock's attempt to halt its spread and cover their actions.
Daniels learns about Operation Clean Sweep, a plan for the military to bomb Cedar Creek which has been approved by the President; now-Major General Donald McClintock plans to use the operation to conceal the virus's existence. To prevent Daniels from finding a cure, McClintock has him arrested for carrying the virus. Daniels escapes, and he and Salt fly a helicopter to the ship which carried Betsy. Daniels obtains a picture of Betsy and releases it to the media; Mrs. Jeffries realizes that her daughter Kate has been playing with Betsy in their yard and calls the CDC. Daniels and Salt arrive at the Jeffries' house, and Salt tranquilizes Betsy after Kate coaxes her out of hiding. When he learns from Daniels about Betsy's capture, Ford delays the bombing.
On their return flight, Daniels and Salt are chased by McClintock in another helicopter, and Salt fires two rockets into the trees to trick McClintock into thinking that they crashed. In Cedar Creek, Salt mixes Betsy's antibodies with Ford's serum to create an antiserum; although Schuler has died, they save Keough. McClintock returns to base and resumes Operation Clean Sweep, refusing to listen to Ford (who wants to cancel it).
Daniels and Salt fly a helicopter in the path of the bomber, which is commanded by a pilot codenamed Sandman One. With Ford's help, Daniels persuades Sandman One and his co-pilot to detonate the bomb over water and spare the town. Before McClintock can order another bombing, Ford relieves him of his command and arrests him for withholding information from the president. Daniels and Keough reconcile, and Cedar Creek's residents are cured.