In the opening scene, Cassie Sullivan (Chloe Grace Moretz) is walking through the woods with a gun in her hands. She comes across an empty store and takes what little supplies she can get her hands on. A voice is heard calling for help. Cassie finds a man hidden in the back. They both have their guns aimed at each other. The man lowers his gun but Cassie won't lower hers because the man is holding something in his hand. She orders him to show what's in his hand, but when he does, a light flashes from it and startles Cassie, prompting her to shoot the man. She sees that he was holding a crucifix, and she is horrified at what she's done.
Several months earlier....
Cassie was a regular 15-year-old teenager in high school girl. She lived with her parents Oliver (Ron Livingston) and Lisa (Maggie Siff), and her little brother Sam (Zackary Arthur) in a suburb of Cleveland, Ohio. Her best friend was Lizbeth (Gabriela Lopez) and she had a crush on football player Ben Parish (Nick Robinson). Soon, however, everything changed as a mysterious alien spaceships descended and remained hovering above everyone for a number of days without movement. The humans would come to refer to these visitors as "The Others".
The Others unleash the first wave, which is an electromagnetic pulse that wipes out all the power on Earth. Planes fall from the sky and kill countless people. Without a fresh water supply, Cassie and Sam have to gather water from a nearby lake.
The second wave brings powerful earthquakes and devastating tsunamis to coastal cities, killing even more people.
The third wave has the Others modifying the avian flu, which infects people like Lizbeth and even Lisa. Cassie, Sam, and Oliver bury Lisa in the front yard of their house and say goodbye to her.
The three head to a survivors camp. After a few days of residing in the camp, a large cloud of dust forms, and from it emerge military men in vans, led by Colonel Vosch (Liev Schrieber). He says he's there to help them. They gather all the children and send them on a bus to a safe location. Oliver reluctantly lets Cassie and Sam go. Sam forgets his teddy bear, so Cassie runs off the bus to grab it. The buses start driving away before Cassie can make it back.
Vosch tells the adults that the fourth wave has begun. The Others have begun to use humans as physical hosts, inciting anger and panic among the adults that demand to know how they can tell who is really an Other. A gunfight breaks out, and nearly every adult is killed, including Oliver. Cassie mourns her father and proceeds to move forward on her own.
The kids arrive at Camp Haven, a military training facility. Ben and Sam are among those that are recruited. They are given new nicknames as well - Ben is "Zombie" and Sam is "Nugget". Ben meets Sergeant Reznik (Maria Bello). She injects a tracker in the back of his neck and sits him down in front of a two-way mirror where a boy is hooked up to a chair. Reznik says the boy is really an Other. She shows Ben through a lens that the boy has a green skull, then gives Ben a button to kill the boy. Reznik sees that Ben is wearing his dead sister's necklace, using it as motivation to push Ben to press the button, which he does.
Cassie carries a gun that her father gave her before he died. She arrives at the abandoned convenience store in the opening scene and is forced to shoot and kill the wounded man as seen before.
Next, Cassie walks through an abandoned freeway littered with many abandoned cars and sees many dead bodies. A shot is fired, hitting Cassie in the leg. More gunfire is heard, and Cassie crawls to safety under one of the cars before she passes out from blood loss.
Meanwhile, Ben and the other kids start their training. He befriends another kid named Dumbo (Tony Revolori), and they are presented with a girl called Ringer (Maika Monroe), who is tough and takes crap from no one. She is an excellent shot, and she teaches the kids how to shoot after Ben takes her down during training.
Cassie wakes up to find herself in the care of a young man named Evan Walker (Alex Roe). He tends to her gunshot wound. Cassie wants to leave and find Sam, but Evan warns her that it would be dangerous for her to go out there on her own without protection. Cassie discovers that Evan took her gun and hid it. She runs away but sets off one of his traps in the woods. Evan runs back to her and protects her as someone else with a gun is walking through the woods.
At Camp Haven, Colonel Vosch brings Ben into the control center and tells him that the fifth wave is already happening. He gives him a helmet that will allow him to detect an Other so that he can easily kill them.
Evan teaches Cassie how to defend herself by showing her how to take someone's gun and incapacitate them. She shows him pictures of the people she used to know and love before the invasion. Quickly, Cassie and Evan develop an attraction for each other.
The kids are brought to a location where Others have been detected. They spot a number of people with green skulls and fire at them. However, they then see Ringer through their lens and see a green skull. Before anyone can shoot her, Ben stops them. He is spotted with a green skull too. He quickly realizes that Vosch and Reznik lied to them, and that THEY are really Others. The fifth wave is the kids themselves. Since they are easily manipulated, they are being used as pawns to slowly wipe out the rest of the humans.
Cassie learns that Evan is not quite human after witnessing him kill someone in the woods. He claims that when the alien ship arrived, a switch went off in him. He says he saved her when she got shot from someone else in the distance. Evan claims that his love for Cassie is making him more human. She runs from him and is rescued by the military.
Cassie is taken to Camp Haven and goes through the same process as the other kids, only this time she can immediately spot something suspicious with Reznik. The two of them fight until Cassie knocks Reznik out.
Ben confronts Vosch about the truth, to which he confirms that he and the rest of the military personnel are Others, and that they need the Earth for themselves. The base is then infiltrated. Cassie runs into Ben, and is then reunited with Sam. Evan shows up and kisses Cassie one last time before he goes to blow up the facility. The heroes run outside as the place is blown up. Ringer rescues them in a van, and they drive away, while Cassie watches as the place is destroyed, sad for Evan's sacrifice. But Colonel Vosch and the rest of the infected military and child cadets escape in a fleet of helicopters and fix-wing aircraft.
The kids then set up their own camp, with some of the other kids like Dumbo joining them. Cassie closes the film by narrating that they haven't lost hope, and that hope is keeping them alive.