Set roughly in present day Dayton, Ohio, The 5th Wave follows 16-year-old Cassie Sullivan as she tries to survive in a world devastated by the waves of an alien invasion that have already devastated the Earth's population and knocked humankind back to the Stone Age. She is headed to a "training" facility established by the aliens in the hopes of saving her five-year-old brother, Sam, who was taken there.
Cassie comes across a gas station where she finds a wounded soldier. She kills him after mistaking the metal in his crucifix for a gun. This intensely disturbs her. While on an Ohio highway, on her way to find her brother, she comes across the recently deceased. Cassie is then suddenly shot in the leg by an unknown sniper. She takes cover under a car and has to make a difficult choice: try to flee the area and risk being shot by the sniper, or bleed to death under the car.
The plot then jumps to Ben Parish, Cassie's crush in high school, who is sick with the disease spread during the 3rd Wave; he is tended to by a friend named Chris. Ben is taken by soldiers to a woman named Dr. Pam and miraculously recovers from his disease. Dr. Pam tells him the Others raided his camp, Camp Haven at Wright-Patterson Air Force Base, by inhabiting human hosts and posing as refugees. Dr. Pam puts Ben through a program called "Wonderland" and takes him to a hospital room, where Chris sits wired to a chair. Dr. Pam lets Ben look through a special eyepiece to find that a creature is attached to Chris's brain, which Dr. Pam confirms is an Other. She explains to Ben that the only way to kill the creature inside is to kill the host, which Reznik, a senior drill instructor, pressures Ben into doing.
Commander Vosch, who killed Cassie's father at their refugee camp, meets Ben in his room. Vosch is straightforward and tells Ben they will all die, but not without a fight. He gives Ben a position in Camp Haven's new army, and he becomes Private Zombie. Cassie awakens in a four-poster bed hooked up to an IV machine and with her wounds nearly healed. She meets her savior, Evan Walker, who tells her they are in his rural country house, and he'd found her on the highway, crawling in blood. Cassie insists that she must go to Camp Haven to save her brother, but Evan is unsure that she is fit enough for the journey yet, and so they stay. Over time, the two grow closer. One night, Cassie and Evan get into a fight, but Evan ends it by saying that Cassie saved him, rather than vice versa, and kisses her.
Sammy Sullivan, Cassie's brother, has arrived at Camp Haven via the bus on which he was taken. The soldiers at Camp Haven mark the children: greens for unhealthy, reds for healthy. Sammy is marked red. He is called to be processed and cleaned. He is put through the Wonderland program and asked many questions relating to his personal life. After Sammy is fully processed, Dr. Pam offers to let him see an Other.
Ben Parish, now Private Zombie, has been assigned to squad 53. His squad sergeant, Sergeant Reznik, is a cruel, uncaring man who taunts his members about their personal lives, which he learned about via the Wonderland program. He takes a liking to a member of another squad. Another member is added to squad 53, Sammy Sullivan, whom Reznik calls "Private Nugget". Reznik taunts Nugget, Zombie blurts out, "Leave him alone!", and Reznik punches Zombie in his throat, but respects his spirit and appoints him as the new leader of squad 53.
During a fire drill at Camp Haven, Nugget is scared, so Zombie slings him on his shoulder and runs with him. Zombie slows the squad down by 45 seconds, angering them. Private Tank goes "Dorothy", (meaning crazy), and pulls his gun out. Private Flintstone takes Tank down before anyone is hurt. Tank is later found dead in the P&D (Process and Disposal) hangar and is replaced by Private Ringer, whom Zombie had previously taken a liking to. Ringer attempts to improve the squad's marksmanship and succeeds; Squad 53 skyrockets through the ranks and graduates with the other top three squads.
Cassie continuously confronts the dilemma of whether or not to trust Evan. Either way, Evan and Cassie continue building a relationship. While Evan leaves for one of his night hunts, which Cassie suspects are something far more terrible than he lets on, she searches through his things for any evidence that points to Evan's being one of the Others. She finds her M16 in Evan's barn under a blanket, but Evan casually says that he simply found it near her when he found her. After a few more days, Cassie feels she is fit enough for the journey and Evan, against Cassie's wishes, sets out with her, burning his house down as a distraction to the Others.
Zombie and his squad are on their first patrol. They are given special headsets with lenses that can supposedly distinguish between a human and an Other. The squad is attacked, and Private Oompa is killed. Zombie and Ringer pursue their assailants, while Private Poundcake covers them from above with his sniper. While under the cover of a building, Ringer cuts out her implant, and her head lights up green through Zombie's lens. They piece the evidence together and conclude that Camp Haven is not a human training camp, but an "Other death camp". They find that their assailant is Reznik and kill him. Reznik is holding a piece of equipment with a map of green spots: the implants. Ringer and Zombie return to the squad and explain to them what they know. Flintstone, who is skeptical, snatches the equipment away and pulls a switch. He drops dead. Zombie is reluctant to leave whilst Nugget is still at Camp Haven and has Ringer shoot him, so that his story will look real. Zombie is then evacuated by a helicopter to Camp Haven.
While on their journey, Cassie and Evan are attacked by a group of juvenile soldiers. Cassie is shocked as she watches Evan take them down with ease, though he injures his thigh and buttocks in the process. Once the soldiers are taken down, Cassie makes Evan confirm that he is the Silencer who shot her, while he is awkwardly stripping his clothing to treat his wounds. Cassie initially decides to leave him there to bleed to death, but afterwards decides to help him. The two then orchestrate a plan wherein Evan has little involvement, though he strongly disapproves of this.
Cassie arrives at the base on a bus and is called for processing. Dr. Pam meets with her, and Cassie knocks her unconscious. While Cassie is trying to locate Sammy, Dr. Pam awakens and commits suicide. Zombie awakens in a hospital bed and sees Vosch, who tells him that Zombie will be put through Wonderland. After Vosch leaves, Zombie escapes and steals an outfit from a dead guard. Cassie finds Sammy/Nugget and meets Zombie, but the three are captured by Vosch. Vosch attempts to kill Nugget by electrocuting him.
It is revealed that Evan has planted bombs and hacked into the base's mainframe. When Vosch heads to Control, Evan appears and kills the soldiers guarding Zombie, Cassie, and Sam. Evan says goodbye before allegedly setting off "eyes", the same bombs Vosch used to destroy Cassie's refugee camp. The members of Squad 53 arrive and save Zombie, Cassie, and Sam. They ride off as Camp Haven is destroyed.