Cassie Sullivan, armed with an M4, emerges from the woods to raid an abandoned gas station. While searching the store, she hears a man calling for help. She investigates and finds an injured man in the storeroom, pointing a gun at her. She tells him to put his weapon down, and he does so. He then tells her to drop her weapon. She is wary, because she can't see his other hand under his jacket. She demands he pulls it out, but as he slowly moves it, she sees a glint of metal, and shoots him. But it turns out that he had his hand on a wound while holding a crucifix on a chain wrapped around it. Cassie gasps in shock and then the screen cuts to black.
Cassie is at a party with her friends and her voice-over states this was her last day of living a normal life. The next day the media is all about a large alien craft slowly floating over the planet. Her family goes outside to see the strange spaceship, which everyone has dubbed "The Others." Cassie goes back to school for several days, while many families have fled the city. The power cuts off due to an electromagnetic pulse from The Others, which is the first wave. Cassie witnesses vehicles, cell phones and even watches losing power. The class witnesses a large passenger airplane falling from the sky.
While out collecting water, Cassie and her little brother, Sammy, are caught by a quake and tsunami. They manage to climb a tall tree, avoiding the flood waters. This was the second wave. The Others dropped a large metal spike from orbit directly onto Earth's fault lines causing massive tsunamis worldwide, wiping out every coastal city and island.
Cassie's narration continues, stating there there are over 300 billion birds in the world. In the third wave, The Others genetically modified the avian flu virus, creating a far more virulent plague. Cassie's school is now a quarantine field where her mother works. When Cassie comes to volunteer, her mother demands that she leave to take care of her young brother. Later, the family is seen standing at her mother's grave, mourning their loss to the plague. After the third attack, Cassie's family packs their stuff and leave the house.
They find a refugee camp housing the last survivors in the area. Cassie's dad gives her a Colt .45 pistol for self defense. Cassie says that she thought the camp was safe, but her dad replies that nowhere is safe. Later, the US Army, led by Commander Vosch, shows up with an order to escort everyone to safety. The Army separates the children, evacuating them on school buses, while the adults are gathered in the field house for an intelligence briefing. Cassie rushes back to her bunk to retrieve Sammy's teddy bear, but is too late, as the busses drive off without her. Commander Vosch tells the adults that the 4th wave has just begun. The Others have landed on Earth and like parasites, have taken over human bodies as hosts. This causes hysteria among the survivors, who begin firing their weapons. Eventually, the army kills all the adults, with Cassie witnessing her father's death. She decides to follow the buses on foot so she could be reunited with her brother.
Sammy and the other children arrive at a military camp, where he is attached to Squad 53, along with Ben Parish, Dumbo, Oompa, Ringer, Teacup, and Pound Cake. The camp personnel tell the children that they are needed to fight The Others. They are implanted with tracking devices in their necks, supposedly to indicate that they are human and not hosting the alien parasite. Through a one way mirror Ben is shown a teenager in a stupor. He is given a visor that shows a parasite latched onto the teen's brain. He is offered the chance to kill the alien at the cost of also killing the host with the push of a button. He does so, and passes the test to see whether he is willing to kill the aliens.
The scene where Cassie comes across the abandoned gas station is partially repeated, bringing the story up to date. Cassie travels further down the highway, where she finds bodies with gunshot wounds in their heads. Cassie is then shot in the leg by an unknown sniper. She hides under a car, regains composure and makes a wild dash, blindly firing her pistol. However, she eventually faints. Cassie wakes up in a farmhouse where she meets Evan Walker. Evan claims to have rescued Cassie and tends to her wound, but Cassie is suspicious. She later finds her pistol hidden in another room, and attempts to flee. While escaping, she trips over a wire attached to an improvised alert system. Evan races out and restrains Cassie, hiding them hide behind a tree. An alien craft then flies overhead, searching the vicinity. Evan explains that they are hunting for survivors and he had to hide Cassie's pistol for his own safety. Despite Evan's belief that Sammy is probably dead, Cassie insists on continuing her search and Evan accompanies her. Gradually, Cassie falls for Evan and kisses him.
At camp, the young people are being trained to kill. They are sent on a mission to eliminate any nearby Other hosts, equipped with visors that identify the carriers (outlined in green). Ben claims Sammy has food poisoning, but it's shown that Sammy is tied up in the toilet, shouting for help. Oompa, one of the Squad 53 members, is killed and the squad falls under heavy fire. They seek cover in a nearby building, where Ringer declares that it's doesn't make sense that the Others, with their vast abilities, should be afraid of an army of children. She then pulls her tracker out of her neck, which causes her image in the visors to suddenly show an alien parasite. Ben does the same and also appears green in the visors. They realize that their army superiors are the Others and the children are being duped into killing human survivors. They are the 5th wave. The squad decides to go off grid. Ben heads back to the army camp to rescue Sammy, while pretending to be the squad's lone survivor.
Cassie and Evan encounter guards near the camp. Evan shows superhuman strength and Cassie figures out he is an Other. Evan explains that she is wrong - he is "both" the Other and the Human, a kind of hybrid. Such agents were placed on Earth by the Others years before the invasion, Evan was hearing "the voice" in his head from his early days, and after the Others arrived they assumed direct control of their agents. Evan confesses that he loved Cassie at first sight, and she invoked feelings in him that made him resist being controlled by the Others and he has been tracking and protecting her for some time. He also confirms that the use of the human children is the 5th wave.
Cassie forces him to leave her, because she doesn't trust him anymore and she infiltrates the camp alone. She kills one of the Others who was implanting the tracking devices, and dons its uniform. At the same time, Vosch sees through Ben's ploy and they have a heated argument. Suddenly, the camp is under attack by an unknown force. Ben flees and bumps into Cassie, and they both start looking for Sammy. Evan then appears and subdues some Other guards. He then confesses his feelings for Cassie and they share a kiss. Evan reveals that he is the camp's attacker and the bombs he planted will destroy the entire camp. He leaves to resume the attack, while Cassie and Ben eventually find Sammy.
The rest of the children at the base are evacuated in planes. Vosch and his men abandon the base and leave in helicopters. Ringer arrives in a Humvee to rescue Cassie, Sammy and Ben, just as the camp is destroyed. They meet up with the rest of Ben's rogue squad to plan their next moves while Cassie narrates that hope is the humans' defining character trait.
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