On Black Friday 2015, a viral epidemic, transmitted by a smallpox-based virus planted on banknotes, sweeps through New York City. The disease, known as "Green Poison" or the "Dollar Flu", causes widespread chaos, and major cities across the United States are placed under quarantine. Facing the collapse of law and order, the United States government activates sleeper agents in the population who work for the Strategic Homeland Division (SHD; or simply "the Division"), to assist the Joint Task Force (JTF)—a combined task force of police, fire and rescue, National Guard, disaster response organizations, and civilian volunteers—in restoring order. However, the first wave of agents deployed to New York City goes AWOL, forcing the deployment of a second wave.

The second wave, including the player Agent and fellow agent Faye Lau, are preparing to deploy to Brooklyn when the aircraft meant to take them there explodes, killing the Division Commander and most of the second wave, and wounding Lau. Deploying from a JTF helicopter instead, the Agent reclaims the James A. Farley Building to use as their base of operations. From there, the Agent undertakes assignments to assist and rescue personnel, restore the base to full working capacity, and combat New York City's dominant criminal groups: the Rioters, common street thugs attempting to take advantage of the quarantine; the Rikers, sadistic escapees from Rikers Island; and the Cleaners, Department of Sanitation employees who seek to "purify" whatever they deem infected using incendiary weapons. The Agent eventually recovers a sample of Green Poison, and learns it was manufactured and modified by controversial biologist Dr. Gordon Amherst. They also learn of rogue Division agent Aaron Keener, who broke down and defected alongside the first wave to assist the Last Man Battalion (LMB), a private military company hostile to the Division.

Intercepting a signal from the Russian consulate, the Agent attempts to rescue Vitaly Tchernenko, a Russian virologist who claims to have information on the Green Poison; however, he is kidnapped by Keener and the LMB before they can reach him. After helping the JTF secure supplies and weapons, the JTF and the Agent assault the LMB's base, the now-evacuated Headquarters of the United Nations, but Keener and the agents abandon the LMB, taking Tchernenko with them. The leader of the LMB, Charles Bliss, initially escapes in a helicopter, but returns to make a last stand alongside his men and is killed in a battle with the Agent. In the aftermath, Lau informs the Agent that most threats are destroyed or weakened, the LMB was split into factions, and New York City is approaching stability.

Later, an unknown signal leads the Agent to a secluded laboratory, where they find Amherst's remains and learn he died from the Green Poison. The Agent is informed that the information in the lab will further the development of a vaccine and is shown a recovered message from Amherst, stating he developed Green Poison as part of his eco-terrorist plan to decimate humanity to preserve the environment. The Agent also finds a message from Keener, who reveals he intends to develop a new strain of the Green Poison, and suggests the Agent travel to the "Dark Zone", the chaotic center of Manhattan. If the player does so, they will discover a message from Keener, who announces he plans to continue Amherst's plan, and offers the Agent a position beside him based on their actions in the Dark Zone.