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.

With Nora gone, Eph reluctantly joins Setrakian's quest in hopes of gathering enough evidence to warrant a citywide quarantine. Fet encounters the unexpected inside the subway tunnels, and a medical emergency threatens Palmer's master plan.

Setrakian, Eph, and Nora formulate a plan to track down the Master using Jim as bait. Eichhorst and Setrakian’s pasts are revealed. At the Luss home, Neeva struggles to protect the children while encountering a mysterious stranger whose help she may not want.