When a plane lands in New York City with everyone on board dead, Dr. Ephraim Goodweather, head of the CDC’s Canary Project, and his team are called upon to investigate. Harlem pawnbroker Abraham Setrakian races to the airport, convinced that what looks at first like a mysterious viral outbreak might be the beginning of something infinitely more sinister.

The four survivors begin manifesting strange symptoms, but Eph and Nora's attempt to quarantine them is thwarted as the disinformation campaign begins. Meanwhile, in jail, Setrakian receives a surprise visit from an old - a very old - acquaintance.

Eph and Nora fight to save Captain Redfern's life before coming face-to-face with the horrifying effects of the virus. A spike in rat attacks signals Fet that something inexplicable is happening deep below the city. Released from jail, Setrakian begins his own merciless plan to stop the spread of the disease.

After warning Kelly to leave the city with Zack ahead of the spreading plague, Eph is arrested by the FBI. Eichhorst has one final job for Gus, while Setrakian realizes that the coming eclipse is the tipping point for virus infection and the beginning of the end.

Eph races to safeguard his family, only to learn that Kelly is missing. Dutch reveals her role in Palmer’s plan, and Gus is forced to make a difficult decision about Felix.

Eph investigates Kelly’s disappearance and struggles with what he finds. Dutch pursues a plan to retaliate against Palmer, and Fitzwilliam makes a surprising choice.