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The film follows several interacting plotlines, with no single protagonist, over the course of several weeks from the initial outbreak and attempts to contain it, to panic and decay of social order, and, finally, to the introduction of a vaccine.
Beth Emhoff (Paltrow) returns from a business trip to Hong Kong, after briefly stopping in Chicago to cheat on her husband with an old flame. At first she appears to have contracted a common cold during her trip. Her son, Clark, also begins to show cold symptoms. Clark is sent home from school for the illness, which exposition later tells us he spreads to the school nurse (and thus, the rest of the school). Beth's condition worsens and two days later she collapses with severe seizures in her Minneapolis home; Beth's husband, Mitch (Damon), rushes her to the hospital, but she simply has more seizures there and dies from an unknown virus. Because it affects the brain and central nervous system, they call it a meningoencephalitis virus. Mitch returns home and finds that Clark has also died from the unknown infection. Mitch is put in isolation but turns out to be immune to the disease. He and his daughter attempt to flee the city, but a military quarantine has been imposed, and they are forced to return to their home to face decaying social order and rampant looting of stores and homes. Mitch struggles to balance his daughter's frustration with quarantine with his desire to protect her, while trying to come to terms with his own loss.
In Atlanta, representatives from the Department of Homeland Security meet with Dr. Ellis Cheever (Fishburne) of the Centers for Disease Control and Prevention and express fears that the disease is a bioweapon intended to cause terror over the Thanksgiving weekend. Cheever sends Dr. Erin Mears (Winslet), an Epidemic Intelligence Service officer, to Minneapolis to begin the investigation. Dr. Mears has to negotiate with local bureaucrats reluctant to commit resources and becomes infected with the disease after being in contact with contaminated fomites while staying at her hotel. The Minnesota National Guard arrives to quarantine the city, and a badly deteriorating Dr. Mears is moved to the field medical station she helped set up, where she later dies.
Investigations into cures via treatment protocols or vaccines initially prove fruitless as scientists cannot find a culture to grow the new virus, which has been named the Meningoencephalitis Virus One (MEV-1). Professor Ian Sussman (Elliott Gould) violates orders from a CDC scientist, Dr. Ally Hextall (Jennifer Ehle), to destroy his samples and identifies a line of bat cells that will support research of a vaccine. At the CDC, Dr. Hextall uses this breakthrough to begin to characterize the properties of the virus, which turns out to have a mix of genetic material from bat, pig and human viruses and appears to spread via fomites with a basic reproduction number of two.
A conspiratorially minded freelance internet journalist, Alan Krumwiede (Law), posts the first video blogs about the disease, and in one of them apparently appears sick and later claims that he recovered using a homeopathic cure called forsythia. Panicked people attempting to obtain forsythia overwhelm pharmacies and also accelerate the contagion as infected and healthy people congregate. Krumwiede leaps to national attention and, during a television interview, accuses Dr. Cheever from CDC of informing friends and family to leave Chicago before a quarantine is imposed. It is later revealed Krumwiede was never sick with the unknown virus but was attempting to boost demand on behalf of investors in the companies producing and distributing the homeopathic treatment. He is taken by the police accused of conspiracy and fraud, but is soon released after his 12 million blog readers collect and pay his bail. Krumwiede is last seen returning to his internet journalism, interviewing the people attending the MEV-1 vaccination lines and questioning the safety of the rushed immunotherapy treatment and its yet unseen secondary and adverse effects.
Dr. Hextall identifies a potential vaccine, using an attenuated (live) virus. Because of the difficulties of human subjects testing, she follows the precedent of other vaccine researchers and inoculates herself first. Hextall visits her gravely ill father in the hospital to expose herself to the virus and test the vaccine. Production of the vaccine is rapidly ramped up, and the CDC awards vaccinations via a random lottery based on birth dates for one full year until every survivor is vaccinated.
Dr. Leonora Orantes (Cotillard), is a World Health Organization epidemiologist who travelled to Hong Kong to find out where the sickness originated. While there, she identifies Emhoff as patient zero. Epidemiologist Sun Feng (Chin Han) kidnaps Orantes to use her as leverage to obtain the first MEV-1 vaccines for his village. After the vaccines arrive, Feng exchanges Orantes for the vaccines, which turn out to be placebos. Orantes rushes away when she is informed of this.
Dr. Cheever, feeling guilt over his past actions to protect those who are close to him, gives his fast-tracked MEV-1 vaccination to the son of a janitor he works with at the disease center. Dr. Hextall places the surviving samples of the MEV-1 virus in cryogenic storage with H1N1 and SARS.
The film concludes by showing how the virus originated. Emhoff's mining corporation is clearing the jungle, and a bulldozer knocks over a palm tree in which infected bats were nesting. They fly out and one bat, the vector, lands on a banana plant, eating a chunk of banana. Not having its tree to return to, the bat flies to a nearby hog building, where it drops the banana into a pig sty, where a pig eats it and acquires the bat virus. The pig is then sold and slaughtered and is shown being prepared by a chef in the Macau casino Beth Emhoff visited. The chef smears the pig's blood on his apron but does not wash his hands before shaking Beth's, thereby infecting her with the mutating pig and bat viruses and creating a new human variant, the MEV-1 strain.