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In the northeastern U.S., people suddenly begin committing suicide en masse. First they become disoriented, then stop moving, and finally find the quickest way to kill themselves. The pandemic begins in parks, and quickly spreads to nearby population centers. It is initially believed to be a bioterrorist attack, but this is ruled out as the events increase in frequency.

Elliot Moore (Mark Wahlberg) is a science teacher in Philadelphia. After the school is informed of the pandemic, he decides to leave the city with his wife, Alma Moore (Zooey Deschanel), and his fellow math teacher, Julian (John Leguizamo), who is also bringing his eight-year-old daughter, Jess (Ashlyn Sanchez). The train soon stops at a small town in western Pennsylvania; train services are discontinued after the crew loses contact with "everyone." Julian finds out that the "attacks" have hit Princeton, where his wife is currently headed, and leaves Jess with Elliot while he hitches a ride in an attempt to retrieve her. However, it has already been hit by the pandemic, and a hole in the car's roof exposes them.

Meanwhile, Elliot, Alma, and Jess manage to hitchhike with a botanist and his wife; the man explains his theory that plants are attacking people as a defense mechanism. He elaborates on the complex mechanisms that often seem to appear spontaneously, involving strategies such as attracting predators to kill off specific threats and fostering communication between different species of plants. As they drive, they find themselves surrounded on all sides by affected towns. A number of other cars arrive in the same location. A soldier, Private First Class Auster, suggests moving away from the population centers on foot to avoid any attacks, as the pandemic has been occurring in smaller and smaller populations.

The group of survivors splits into two, with Elliot, Alma, and Jess in a smaller group. Auster's group is struck by the pandemic within earshot of Elliot, and he concludes that it is likely caused by an airborne neurotoxin exuded by the surrounding plants. The larger the group of people, the more likely it is to trigger the defense mechanism. Elliot makes the group split into three smaller ones with Elliot, Alma, Jess, and two teenage boys staying together.

While looking for food for Jess, Elliot's group finds a boarded up house with survivors inside, still believing the pandemic to be a terrorist attack. They are unwilling to open the doors. When the two teenage boys begin to aggressively force an entry, they are shot dead. Elliot's group is forced to leave. They make their way to the house of an elderly woman, who lives in complete isolation; thus, she is ignorant of the pandemic. Though she allows them to stay, she proves to be a harsh host and a paranoid woman once she sees Elliot "eyeing her lemon drink". In the morning, Elliot finds himself alone; going downstairs, he hears the voices of Alma and Jess but cannot find them. He inadvertently enters the old woman's room and she angrily insists that they leave immediately.

The woman storms out of the house into the garden, where she is affected by the neurotoxin. Realizing that the defense mechanism has become even more sensitive, Elliot locks himself inside the house. Elliot finds himself in a room where he can hear Alma and Jess. He finds a speaking tube, which leads to a shed outside the house. Conversing with his wife, he says that he would want nothing more than to be with her. They relinquish themselves to their fate, but the neurotoxin doesn't affect them: the pandemic is over.

Three months later, Elliot and Alma have adjusted to a new life with Jess as their adopted daughter. On television, an environmentalist warns that the pandemic may only have been a warning, like a rash that precedes an infection. Elliot takes Jess to the bus stop for the first day of school while Alma stays at home, timing a home pregnancy test. When he returns, Alma greets him with a smile, and they embrace. In the Jardin des Tuileries in Paris, the pandemic appears to happen once again as everyone in sight suddenly stops moving as the wind suddenly moves the trees.