Eleven years after the events in Burma, Vietnam War veteran John Rambo lives in Bowie, Arizona at his deceased father’s horse ranch, which he manages with his old friend, Maria Beltran, and her granddaughter, Gabrielle. Gabrielle tells Rambo that a friend of hers, Gizelle, has found Gabriela’s biological father, Manuel, in Mexico. Both Rambo and Maria tell her not to go to Mexico, but Gabrielle secretly drives there to ask why Manuel abandoned her and her mother years ago. Gizelle leads Gabrielle to Manuel’s apartment, where he coldly tells her that he never cared for Gabrielle or her mother.
Gizelle takes a heartbroken Gabrielle to a nearby club, where Gabrielle is drugged and kidnapped by the enforcers of a Mexican cartel. Meanwhile, Maria informs Rambo of Gabrielle’s disappearance in Mexico. Rambo rushes to Mexico and interrogates both Miguel and Gizelle about Gabrielle’s whereabouts. After threatened by Rambo, Gizelle reluctantly leads Rambo to the club where Gabrielle was last seen and confronts El Flaco, the man who last spoke with Gabrielle. A mysterious woman, Carmen Delgado, tails Rambo as El Flaco leads him to Gabrielle’s location. Rambo is immediately confronted, beaten and marked by the cartel, led by the brothers Hugo and Victor Martinez. They take his driver’s license with the location of Rambo’s ranch and a photo of Gabrielle, whom Victor recognizes. The cartel vow to mistreat Gabrielle further due to Rambo’s actions.
Carmen takes Rambo back to her home where she cares for him until he fully recovers after four days. While Rambo is cared for by Carmen, Gabrielle is stripped and consistently dosed with heroin and sold to be raped repeatedly. Carmen says she is an independent journalist who has been investigating the Martinez brothers, who kidnapped and murdered her sister. Rambo later raids one of the brothels, killing several men until he finds a drugged Gabrielle. While driving back home in his pickup, Rambo thanks Gabrielle for giving him hope for ten years but she dies from the forced overdose. An enraged Rambo sends Maria away and rigs the ranch with traps for a confrontation, and later returns to Mexico to ask for Carmen’s help in finding Victor. Carmen initially refuses and tells Rambo that it will solve nothing, but is convinced after he appeals to her grief and frustration.
Rambo raids Victor’s home, killing several guards and decapitating Victor. In retaliation, Hugo leads a group of hitmen to Rambo’s ranch, where each falls victim to the rigged traps. Saving Hugo for last, Rambo mutilates him and rips his heart out. In the aftermath, a weakened Rambo sits on the porch of his father’s house, vowing to continue fighting and keep the memories of his loved ones alive. During the credits, flashbacks to scenes from the first four movies in the franchise are shown, with Rambo saddling up his horse and riding off into the sunset.