Businesswoman Beth Emhoff returns from a Hong Kong trip feeling slightly ill. After a layover in Chicago, she returns home to Minneapolis, where she suffers a seizure and dies from an unknown illness. Her husband, Mitch, discovers their 6-year-old stepson, Clark, has also died. Mitch is found to be naturally immune and quarantines his teenage daughter, Jory, to protect her.

In Atlanta, the Department of Homeland Security consults with Dr. Ellis Cheever from the CDC, fearing the illness might be a bioweapon. Dr. Erin Mears is sent to Minneapolis to trace Beth’s contacts and coordinate a public health response. She eventually becomes infected and dies as the virus spreads, causing widespread panic, looting, and violence.

Dr. Ally Hextall at the CDC identifies the virus, MEV-1, as a combination of pig and bat viruses but struggles to grow it in a cell culture. Despite orders to destroy his samples, Dr. Ian Sussman finds a viable culture, leading Hextall to develop a vaccine. The virus is highly contagious, spread through respiratory droplets and surfaces, with a high mortality rate projected to infect 1 in 12 people globally.

Conspiracy theorist Alan Krumwiede falsely claims he cured himself with forsythia, causing chaos as people rush to obtain it. He is arrested but bailed out by his followers. Hextall tests the vaccine on herself successfully, leading to a lottery-based distribution of vaccinations. By then, the death toll reaches 2.5 million in the U.S. and 26 million worldwide.

In Hong Kong, WHO epidemiologist Dr. Leonora Orantes traces Beth’s contacts, identifying her as the index case. Orantes is kidnapped by a Chinese official for vaccines, which turn out to be fake. She tries to warn the village upon her release. A flashback reveals the virus’s origin: a bat disturbed by a bulldozer drops an infected banana piece, consumed by a pig later slaughtered, leading to Beth’s infection via a handshake with a chef.