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.

A secret autopsy demonstrates the bizarre progression of the mystery virus, prompting Jim to make a startling confession. Eph and Nora race to find the father of the youngest victim of the plane tragedy, but someone unexpected beats them to it. Ansel, in the grip of disease, takes desperate measures to protect his family.

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.

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.

Dutch returns with a plan to broadcast Eph’s warning about the vampiric plague. However, they face a new threat when Eichhorst launches his own attack against the pawn shop. Palmer receives a special visitor, and Gus gears up for the on-coming fight but discovers there’s another mysterious factor involved.

Eph and Fet recon for an all-out assault that Setrakian assures them will finally kill the Master. Gus aligns himself with a strange new force, one that may swing the fight in an unforeseen direction.

Gus and Vaun wage an attack on Palmer as Eph struggles to connect with Zack. Councilwoman Justine Faraldo vows to bring her extermination policies to the other boroughs.

Eph and Nora finally see their lethal virus in action. Fet takes the security of Red Hook into his own hands while Dutch and Setrakian set off for Staten Island to question Fitzwilliam, Palmer's former body guard.

Eph changes his appearance to leave the city while Nora is left as the reluctant parent for Zack. Dutch and Nora make a deal with Justine to secure Fet's release from jail.

Eph concocts a plan to make and distribute a bioweapon. Gus realizes Angel can be an unlikely ally, and Kelly comes after Nora and Zack.