Na medzinárodnom letisku Johna F. Kennedyho pristane lietadlo, ktorého svetlá nesvieti a dvere zostanú zatvorené. Doktor Ephraim Goodweather, špičkový epidemiológ a riaditeľ Centra pre kontrolu chorôb v meste New York, je na miesto privolaný, aby záležitosť spolu so svojím tímom vyšetril. Na palube objavia dve stovky mŕtvych a štyroch preživších. Do ich práce sa pripletie aj starý muž, ktorý túto situáciu zažil pred mnohými rokmi a vie o neznámej skrini nájdené v nákladových priestoroch. Medzitým neznámy muž plánuje prevoz záhadné skrine z letiska a z márnice zmizne niekoľko tiel.

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.

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.

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.

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.

After discovering the potency of ultraviolet light against the strigoi, Setrakian gains a new and unlikely disciple. A quick trip to a Brooklyn convenience store turns into a deadly all-night siege.

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.

Setrakian leads Eph, Fet and Nora in the hunt for the Master’s lair. Left behind at the pawnshop with Mariela, Zack risks his safety for Mariela's sake.

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.