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Teenager Cassie Sullivan (Chloë Grace Moretz), armed with an assault rifle, enters an abandoned gas station. While searching the store, she hears a man, who points a gun at her. Cassie asks to see both the stranger's hands but the stranger refuses because of his injuries and Cassie subsequently shoots and kills him and he is revealed to be unarmed.
Cassie's backstory commences at her family home, where the news reports a city-sized hovering object over their home in Ohio, which contains invading extraterrestrials referred to as "The Others". Ten days later the invaders permanently disable all electrical power on Earth with an EMP, which disables all electronics, including telecommunications and most vehicles this is the first wave. The Second Wave sees The Others causing massive tsunamis to kill those living in coastal cities. While at a refuge location, Cassie and her younger brother are in an area struck by an earthquake and a flood, yet they escape unharmed.
For the third wave, the invaders weaponize a strain of avian flu using 300 billion birds as carriers of the virus. Cassie then reunites with her mother who works at a flu victim care facility, but her mother has her leave. Cassie's mother later dies from the flu and is buried by the Sullivan family.
In search of a safe community, Cassie leaves home with her father and brother and stumbles upon a refugee camp in the woods. A few days later, an army unit with working vehicles rolls into the camp and places all of the children on a bus. The Colonel leading the unit claims that there is an imminent threat to the camp and that they want to take everyone to the military base. Due to the limited amount of buses, their priority is to take the children to a safe place before coming back for the adults. As the children get on the bus, Sam tells Cassie he left his bear behind and Cassie goes to get it. Unfortunately, while she is getting the bear, the bus leaves without her. Cassie gets separated from Sam, and she watches as her father and the other adult survivors are massacred by the army after being told they would never see their children again.
Cassie scavenges her way toward the base to find her brother, but is shot in the leg by an unknown enemy and passes out. Seven days later, Cassie wakes up and meets a man named Evan Walker, who saved her. Cassie is afraid and pretends to sleep, but Evan tells her that he knows she's awake. Cassie immediately skeptical of Evan, asks where her gun is and Evan tells her that when he found her, he did not see a gun. One day, when Evan is out chopping firewood, Cassie looks around his house, stumbling upon a loose floorboard, where she finds her gun and something she engraved on the side. Knowing that Evan lied, she grabs her stuff and runs as fast as possible into the forest and gets tripped by a wire. Evan runs after Cassie and keeps her quiet as the drones are watching. Cassie tells Evan that she's going to find Sammy and Evan says he's going with her. As the pair travel together through the woods, they have an intimate moment and fall asleep. While Cassie is asleep, an Other says Evan is out of his drone space and gets into a fight with Evan. After Evan kills the Other, he reveals to Cassie that he is both Other and human. He tells Cassie that this isn't the first time the Others have been on Earth and that a long time ago, the Others planted sleeper agents on Earth, Evan being one of them and that after seeing Cassie, he felt as though "a switch" went off and he was more human than Other. After learning that Evan is not human, she leaves on her own to go find Sam, but not before Evan tells her that Colonel Vosch and the army are actually Others, and that the Fifth Wave will use children to eliminate the rest of Earth's survivors by tricking them into fighting humans.
The only thing that keeps Cassie going is the hope that she can save her brother from the training camp established by the army. Ben Parish and her brother are in the same squad and were sent on a mission to kill Others with helmets that have lenses to detect Others and kill them. Ben ties Sammy up in the military base before going on a mission to keep him safe and tells the leaders that his squad is accounted for and telling his squad members that Sammy has food poisoning. As the squad fights the "others," one is fatally shot and Ringer blows up a car to create a distraction while the rest of the squad finds a safe place to hide. Ringer tells the group that she is skeptical of these Others because they aren't scared of much more powerful weapons, but are scared of a bunch of children. Because of this, Ringer takes her tracker out of her neck and her squad immediately says she's an Other. Being forced to decide whether to shoot her or not, the squad asks their squad leader, Ben, whether to shoot Ringer or not. Ben immediately takes out his tracker, and the squad tells him that he's showing up through the lens as an Other too. The squad then finds out that "green" showing through the lens does not mean Other but rather, the "green" signifies human.
The squad figures out that Colonel Vosch and his people are the Others and have sent the children as soldiers (the 5th wave) to kill the rest of the humans. Ben tells the others that he left Sammy back at the base and needs to go get him. He puts his tracker back in his neck and tells his squad to lay-low, asking Ringer to shoot him to create a fake story and tell Colonel Vosch that his squad is all dead. While Ben plans to rescue Sam, Cassie jumps in front of a bus pretending to be a lost child and ends up being taken to the military base. During her medical exam with Sergeant Reznik, she is given exactly the same medical exam as Ben. As Sergeant Reznik tells Cassie to look through the lenses and look ahead to see the Other held by the military, Cassie kills Sergeant Reznik and steals her military uniform, takes her tracker out of her neck and moves around the base to try to find Sammy. Colonel Vosch is skeptical of Ben being shot specifically in a place that hit no vital organs, while the rest of his squad was killed. Colonel Vosch tells Ben to stop lying, and the Colonel reveals that he is an Other and will kill Ben. The military base is exploding and the Colonel tells one of his men to take Ben away and kill him. Ben disarms the soldier and takes his gun while running, he bumps into Cassie, the two try to find Sam and are stopped by two armed soldiers telling them that they are in a restricted area. Through an air duct, Evan disarms and kills both the armed guards. Evan tells Cassie that he cannot be both Other and "human," he can only choose one and because of her, he chooses to be human. After kissing Cassie, Evan tells Cassie and Ben to go find Sam before he blows up the training facility.
The Others are in the process of evacuating and deploying the children to other cities. Cassie keeps moving through the crowd of child soldiers when she sees Sam and puts her hand over his mouth, leading him to an empty room with Ben. The whole military base is being blown up by Evan, and the three have to leave. As they are running away, they see the Colonel getting into a helicopter and one of the soldiers starts shooting at them. There is an earthquake and the ground starts cracking open, as they are about to fall to their death, they see a Humvee pulling up, they run towards the Humvee and see Ringer driving. They jump into the Humvee and get to a safe place. Cassie and Ben talk about what they will do to save the other children, but they decide that they'll think about what to do tomorrow and try to enjoy today. Ben and his squad are enjoying their meal with Cassie, and while the squad talks and has laughs, Cassie's voice is heard narrating saying that hope is what will drive humans to win one day and that it's our hope that makes us human.
