Eleven years after the events in Burma, 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 Gabriela. Maria informs them that her friend Gizelle has found Gabriela’s deadbeat father Manuel in Mexico. Despite their protests, Gabriela secretly travels to Mexico, where Gizelle leads her to Manuel’s apartment. When Gabriela asks him why he abandoned her mother, he cruelly reveals that he never cared for them, breaking Gabriela’s heart.

Gizelle takes Gabriela to a nearby club, where she is drugged and kidnapped by the enforcers of a Mexican cartel. After learning of Gabriela’s disappearance, Rambo rushes to Mexico and interrogates Manuel and Gizelle about Gabriela’s whereabouts. Gizelle reluctantly leads Rambo to the club where Gabriela was last seen and Rambo confronts El Flaco, the man who last spoke with Gabriela. A mysterious woman named Carmen Delgado follows Rambo as El Flaco leads him to Gabriela’s supposed location. Rambo is confronted, beaten and marked by the cartel, led by brothers Hugo and Victor Martinez. They take his driver’s license, revealing the location of the ranch and a photo of Gabriela, whom Victor recognizes. The cartel vows to mistreat Gabriela further due to Rambo’s actions.

Carmen takes Rambo back to her home, where she cares for him until he fully recovers. Meanwhile, Gabriela is repeatedly dosed with heroin and sold into sexual slavery. Carmen says she is an independent journalist investigating the Martinez brothers, who were responsible for the death of Carmen’s sister. Rambo later raids one of the brothels, killing several men until he finds a drugged Gabriela. While driving home, Rambo thanks Gabriela for giving him hope and meaning for the last ten years, but she dies from an overdose. An enraged Rambo sends Maria away, rigs the ranch with booby traps for a confrontation, and later returns to Mexico to ask for Carmen’s help in finding Victor. Carmen initially refuses, telling Rambo it will solve nothing, but is convinced after he appeals to her grief and frustrations.

Rambo raids Victor’s home, kills the guards and decapitates Victor. Hugo leads a group of hitmen to Rambo’s ranch, where the hitmen are killed through booby traps. Saving Hugo for last, Rambo uses his bowie knife, cuts his chest open 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, the flashbacks of Rambo’s battles are shown, with Rambo saddling up his horse and riding off into the sunset.