Thirty-three-year-old paramedic Jonah Vorhies responds to Angie’s emergency call with his partner and finds Ross near death. Jonah’s inexplicable sixth sense reveals what occurred in the bedroom, confirming in his mind the fact that Ross will not survive. At the hospital, Dr. Rachel Hopman takes over, and Jonah senses that Angie is sick as well.

Across the East River, a practicing witch named Lana Bingham shares a moment with her partner, Max Fallon, and the two spark sudden magick. Although she only considers herself a “dabbler” in magick, Lana ignites a candle wick without touching it and then extinguishes the flame. Max is a practiced magician, but he insists that the power is hers.

At the hospital, Katie rushes in with her husband, Tony. Katie insists that her parents were fine hours earlier, but now her father is dead, and Angie is in intensive care. Dr. Hopman allows Katie a brief visit, and Angie mutters delirious warnings before collapsing in a coughing fit. Katie’s stress triggers contractions, and although they subside, she is admitted to the hospital overnight. When she asks Tony to check on her mother, Dr. Hopman confirms to Tony that Angie, like Ross, has also died of the mysterious illness. Tony, desperate to protect Katie and their unborn twins, weeps as snow begins to fall.

By early January, the plague called “the Doom” has killed over 1 million people. The World Health Organization declares a pandemic, and US agencies label the disease an avian flu variant. However, birds near the MacLeod farm test negative even as people die in waves. Over time, various vaccines and fraudulent cures fail, and riots erupt as social order dissolves. In Brooklyn, Tony dies within 72 hours of Angie.

By the second week of January, the fatalities exceed 10 million and include heads of state, including the US president. By the third week, more than 60 percent of Congress lies dead, and global deaths pass 1 billion. Cities collapse into violence. Some people barricade themselves at home, while others turn to raiding and looting. Throughout the chaos, rumors spread about people with uncanny powers, such as the ability to heal wounds or walk through walls. Air travel ceases entirely, and news reports taper off.

Arlys Reid, a 32-year-old reporter, continues to broadcast as her colleagues die or flee. She lives near the studio, carries a pistol, and documents the wreckage of civilization with only a skeleton crew to support her, including a resourceful intern named Fred. Now, Arlys scours dwindling sources, noting promises of vaccines alongside news of quarantines and preachers calling the plague a divine punishment.

She consults Chuck, a trusted hacker, who reveals that the global death toll already exceeds 2 billion. He also reports that the presidency has changed hands multiple times and that the virus is not bird flu, as only humans are infected. Warning that military roundups of immune people are coming, he urges her to flee New York and gives her a coded rendezvous in Hoboken, New Jersey. On the air, Arlys reports the official lines, knowing that she is lying but telling herself that she is protecting her source and her crew.

Lana listens to Arlys’s broadcast while watching a city in decline. Raiders loot stores and prowl the streets as her neighbors vanish. At the same time, new phenomena emerge, such as people sprouting wings, children controlling lights, and sparks dancing outside her windows.

Lana’s partner, Max, finally contacts his younger brother Eric Fallon, who plans to flee westward to a secluded vacation home. Mapping a route north and west, Max convinces Lana to leave New York and find Eric. Lana packs clothes, food, flashlights, knives, and mementos, while Max gathers backpacks, tools, and a handgun.

As they depart, a neighbor, Michelle, levitates dishes in a manic frenzy, and Max pulls Lana away. Outside, a teenage looter attacks with a knife, and Lana instinctively repels her with an unseen force while Max draws his gun. The girl calls Lana “Uncanny” and blames her and her kind for the Doom. Lana and Max flee into a stolen SUV but come under fire from the teenager’s gang. Lana unleashes her power, flipping the motorcycle pursuing them.

Police sirens follow, and Max warns that some officers are hunting the so-called “Uncanny.” Lana uses her newly discovered powers to slow the police car. Ahead, the Park Avenue lift bridge stands raised. Together, Max and Lana force it down just enough to cross and then raise it again behind them. They escape into the Bronx and turn toward Pennsylvania, vowing to survive.

Meanwhile, Jonah wanders around a collapsing Brooklyn emergency room, where Doom victims and the wounded fill the halls. Staff numbers have dwindled while the morgue has filled, and Jonah’s partner, Patti, has either fled or died. Jonah’s constant visions of death have driven him to despair.

He finds Dr. Rachel Hopman in the break room, drawing her own blood. She has been exposed to the virus for four weeks but remains healthy, and she posits that Jonah is immune as well. She tells him that federal military teams are sweeping hospitals, taking immune staff into quarantine. Communication with the Centers for Disease Control and Prevention has broken down. She warns Jonah to leave, but he has only come to say goodbye.

Outside, Jonah is preparing to end his own life when a pregnant woman, Katie, stumbles from a red minivan. She is in labor with twins. Jonah guides her to the deserted maternity floor and prepares warming trays. With no doctor available, he delivers the babies himself. The first infant, Duncan, is healthy and loud. The second, Antonia, is smaller, and she is silent until Jonah clears her airway.

Katie thanks Jonah and calls him her miracle, and he admits that she and the babies saved him from suicide. Rachel arrives and recognizes Katie as the daughter of Ross and Angie MacLeod. Jonah insists that they all escape before the sweeps take them. He proposes using a small boat to cross the river and move into rural areas. Rachel, exhausted but convinced, agrees to gather supplies and leave the next day if Katie and the babies remain stable.