The film begins with a young boy, Thomas, taken in by Ava Paige (Patricia Clarkson) and troops from the organization WCKD, alongside other children, after being dropped off by his mother for his own safety. In the present day Thomas (Dylan O'Brien) and the remaining Gladers - Newt (Thomas Brodie-Sangster), Minho (Ki Hong Lee), Teresa Agnes (Kaya Scodelario), Frypan (Dexter Darden) and Winston (Alexander Flores) are brought to the desolated city following the Death of Gally the Glader's enforcer, Alby, the first male to enter the Glade and the leader of the Gladers, Chuck, a chubby friend of Thomas and also the youngest Glader, Zart, Jeff and the several others are killed by the Grievers and escaped from the Maze- are taken to a facility run by Mr. Janson (Aidan Gillen). He explains that the facility is a safe haven, protecting them from WCKD, the Flare virus and the Cranks, and provides them clothes, food, and sanitation, where other survivors of multiple mazes are also present. Thomas becomes curious about their activities and manages to find out what is really happening behind the closed doors. With help from Aris Jones (Jacob Lofland), the first maze survivor to end up in the facility, it is revealed that WCKD's leader, Ava, is still alive and that Mr. Janson is working for WCKD, as they discuss about the experiment on the Immunes and that Janson has yet to find The Right Arm, a resistance group located at the mountains. The group, including Aris, escapes the facility, as Janson orders his WCKD troops to track them down, where they find themselves in the deserted outside world - the Scorch.
The group arrive at an abandoned marketplace, where they first encounter with the Cranks, humans zombified by the Flare virus. In the process, Winston gets infected by one of them. When morning comes, they find the city has turned into ruins and that WCKD is still searching for them. Winston's infection gets worse, forcing the rest of the group to leave him alone to die by shooting himself, preventing his transformation. As group continues to venture the desert until one night, while sleeping in the middle of the desert, Thomas awakens and discovers civilization from far away. As a thunderstorm emerges, they run to an abandoned facility to keep them from the storm. Minho gets struck by the lightning, but he survives. They manage to enter the place, only to find out that the facility they entered was filled with chained Cranks. The group meets Brenda (Rosa Salazar) and Jorge (Giancarlo Esposito), who lead a dangerous band of survivors and have used the Cranks as their own guard dogs. When the two find that the group had come from WCKD and is looking for the Right Arm, the two agree to take them to the Right Arm, abandoning their group of survivors. Moments later, WCKD, led by Janson, storms the place, only for the facility to be destroyed by Jorge's explosives, however, Thomas and Brenda are left behind as the rest have escaped with Jorge. Thomas and Brenda manage to escape the Cranks, only for Brenda to get infected by a Crank in the process. Thomas experiences a flashback of when he and Teresa were working for WCKD, in which Thomas tries to warn Teresa of WCKD's plans, only for the two to be separated by WCKD's troops. As Thomas and Brenda reunite with the rest of the group, Jorge interrogates Marcus (Alan Tudyk), a survivor who secretly works for WCKD, into revealing the whereabouts of The Right Arm.
The group eventually arrive at The Right Arm's relief camps, where other innocent survivors are present, and are greeted by Vince (Barry Pepper) who leads the Right Arm and is in charge of deciding whether they can stay or not. As Brenda's infection gets worse, Vince threatens to shoot Brenda, only to be stopped by Mary Cooper (Lili Taylor), a former WCKD scientist who reveals that Thomas was their informant. As Mary halts Brenda's infection using an enzyme cure, Mary explains that the enzyme can only be harvested from an Immune's body, not manufactured, and that arguments over the methods of manufacturing the cure with Ava lead Mary's departure from WCKD. That evening, Teresa calls WCKD of her location, believing that WCKD's motivations are good, leading to an ambush by WCKD. Ava and Janson arrive and confront the Right Arm before WCKD troops captures survivors for experimentation, including Minho, while Janson shoots Mary dead. After Thomas and the Right Arm fend the WCKD troops off, Ava, Janson and Teresa retreat with their captured survivors. With only a fraction of survivors left at the site, Thomas plans an infiltration into WCKD and is determined to take them down to save his friends and save civilization, as his friends and the Right Arm agree to help and prepare to fight back.
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