The film opens in New York. People start to get confused in Central Park, repeating their words, standing still and sometimes walking backwards. We hear a few screams. A woman (Alison Folland) reading on a bench takes her silver chopstick-style hair pin out of her hair and stabs herself in the neck with it. Meanwhile on a building site, workers on the ground are chatting when all of a sudden a body falls. Panicked, thinking the worker just fell off the roof by mistake, they rush over to his broken body. While they looked over the body, another thud, another worker. They look at him confused; one is possible, two is unlikely, and when the third falls, it seems impossible. Then yet another and another, crashing to earth. When they look up they see many running off the edge, apparently by their own will, looking completely calm, and sure of their actions.
In the next shot, we see a science teacher named Elliot Moore (Mark Wahlberg), talking about the event science can not explain about thousands of disappearing bees, no bodies left, no trace. A student offers the opinion that this is a natural event that we will never fully understand. While speculating on the phenomenon that is the disappearing bees, Elliot is suddenly called out of class to a staff meeting warning about an apparent "terrorist attack" in New York in which terrorists have apparently released some kind of gas in Central Park, and advising that school is cancelled. As they leave, Elliot confesses to his friend Julian (John Leguizamo), a math teacher, that he and his wife are having some problems.
Elliot and his wife Alma (Zooey Deschanel) flee Philadelphia on a train, with Julian, and his daughter Jess. On the train people start to get reports by cellphone that the attacks have been reported at their destination, and in many other places. Alma is getting repeated and insistant calls on her phone from someone called Joey, and she lies to Elliot about it.
The movie moves on to show Rittenhouse Park in Philadelphia, where a woman walks her dog and a breeze begins to blow. A traffic cop (Don Castro) walking through a traffic jam stops and comments to a taxi driver about the chilly weather. Suddenly everyone stops in their tracks, and the dog runs across the road after his leash drops to the ground, leading us back to the cop who is now standing still in front of the cab. A gunshot rings out and he drops to the ground. As blood spurts from a bullet wound on his forehead, the taxi driver gets out, walks over to the dead cop, picks up the gun from beside the body and shoots himself in the forehead as well. A woman in high heels steps off the sidewalk, picks up the gun again and we hear another gunshot.
The train ends up leaving Elliott, Alma, Julian, Jess, and all the other passengers in a small rural town, as the conductors have lost radio contact with everyone else. At a diner they see a newscast that suggests the suicides are not caused by a terrorist attack, but by a natural phenomena. A reporter says that the toxin switches off the part of the brain that keeps us from harming ourselves.
Julian has by now lost phone contact with his wife (who was visiting Princeton) and starts to panic as some lady shows Elliot a youtube type video she was sent on her iphone, showing a man walk into a lion's den at a zoo, and taunting the lions with his hands to try to get them to attack him (there's a graphic shot of him staggering with both his arms eaten off). Julian finds a lift with some people heading to Princeton; he leaves Jess with Elliot and Alma. When he gets there Princeton is also infected, and there are dozens of people hanging from trees over the road. The driver of the car crashes deliberately into a tree at high speed and Julian slashes his wrists with broken windscreen glass and dies (this is the one time you don't see anything graphic - the camera cuts away and we see less than the scene in the red band trailer; where you can see Julian bleeding from the wrists).
Meanwhile Elliot and Alma decide, along with everybody else, to flee for the state line with Jess, as the attacks seem only to be affecting the northeast US. A nice couple who run a plant nursery offer to take them in their car. The man suggests to Elliot and Alma that the toxin is produced by plants. He explains the way plants can communicate with other plants, and the way they can release chemicals to get rid of specific pests.
While trying to reach the state line they see bodies ahead in the road. Turning back they meet many other cars, all converging on a country road junction; all report bodies back the way they have come. Organised by an army private they abandon the cars and strike out on foot, heading for a small remote housing development one man (a realtor) knows about. It's new and small and not on any maps except local ones, so they hope it will be safe from the terrorists since it appears they are focusing on large cities and roads.
From the junction one group leaves immediately, but most take a minute to get things from their cars, so walking across the fields they are in two groups. The smaller group (10-12 people), with Elliot, Alma and Jess, is in front. The larger (20-25 people), including the soldier and the plant couple, is behind them by 3 or 4 minutes. This larger group gets infected, and the soldier become delusional (shouting something about how he is a soldier and his gun is his friend, and he will not leave it). Then Elliot's group hears the gunshots as one by one they (presumably) use the soldier's gun to kill themselves. Elliot starts to believe that it is indeed the plants, and that the toxin is triggered by large groups of people. He yells at everyone to split up into smaller groups, and the group peels off into three smaller groups, all running away in different directions.
Alma tells Elliot that if they are going to die, she wants to tell him something. One night, when she had told Elliot she was working late, she actually went out for tiramisu with Joey from work; but that's all that happened.
After walking for a bit, Elliot counters with the fact that he finds the girl who works at the local pharmacy very attractive, and sometimes he buys cough syrup from her even when he doesn't have a cough: he later confesses he made this up.
Elliot, Alma, Jess, and two teenagers find a showhome for the new development. There is some comic relief as Elliot talks to a plant he sees blowing inside, and introduces himself, saying he is giving good vibes so it won't harm him. It turns out the plant is plastic, but he keeps talking for a little just in case - feeling like an idiot. As they leave they look back, and see two small groups of people arrive at the showhome, forming one larger group (12-15 people approx). That many people trigger the toxin, and they stand around confused, except for one man who starts up a large commercial lawnmower, then lies in the grass in front of it as it rips him apart. (We assumed the camera would cut away, but it doesn't! As previously stated, this movie is extremely graphic!)
Our five people all end up on the front porch of a boarded-up house, asking for food, while Jess plays on a rope swing suspended from a tree branch (the swing and the tree seemed very chilling and climactic, but nothing actually happened). The inhabitants of the house refuse to offer food or shelter, and the two teenagers start to get very aggressive, kicking at the door and shouting at the people inside. The inhabitants shoot the two teenagers dead: one through the chest and the second through the head. Elliot is horrified.
Elliot, Alma and Jess move on till they find an old house with no power, which they think is abandoned. A spooky old lady lives there, who chooses to remain out of contact with the whole world. She doesn't want to know about the event in the outside world; however, she gives them supper and a bed for the night.
We (the audience) see a newscast discussing the toxin (our protagonists don't, as the house has no TV). A scientist is suggesting that judging from the severity and number of the attacks, and assuming some similarities to other kinds of natural toxins like ocean algae, the attacks will peak at 9am the next day, and very quickly fall away to nothing following that (there's a graph that shows a drastic tail-off of toxin activity).
In the morning when Elliot wakes up the old lady tells him that he, Alma and Jess have to leave (she seems completely bonkers). She then goes outside into the garden, pauses, and starts walking backwards; the toxin has affected her. As Elliott cowers inside the house the old lady walks around the porch and headbutts the walls, and eventually the window, leaving glass splinters in her face and eye, and also letting in the wind (and the toxin).
Elliot runs through the house trying to find Alma and Jess. He can hear them, but can't locate them. He thinks he hears them in the cellar, but when he goes in he is alone. Alma and Jess are actually outside in an old stone spring house (a remnant from the pre-Civil War Underground Railway). A speaking tube between the spring house and the cellar has transmitted their voices as clearly as if they were right next to Elliott; and Elliott can talk to them through this. He explains that the toxin now seems to be set off by even one person alone.
Elliot decides that if he is going to die he doesn't want to die alone. They all leave their safe hiding places and walk into the middle of the garden and hold hands. The wind blows. Nothing happens. IT had ended.
Three months later and they are all living back in Philly (which looks business as usual; although the streets are fairly empty there are cars driving around, and people walking on the sidewalks). Jess is off to school by bus. Alma is doing a pregnancy test; it's positive, and Elliot hugs her and looks delighted. On the TV is a scientist warning that the event was like a red tide; the first sign that the planet is rejecting humans as pests. The host says that if that were true it would be happening in other places.
Cut to the gardens at the Palace of Versailles in France. Two guys are walking discussing plans for after work that evening. Cue distant scream; one guy starts to repeat his words about a bike, everyone stands still; other guy says (in French) "Oh my God".