Twenty years after the last installment in the film series, John Rambo (SYLVESTER STALLONE) has retreated to northern Thailand, where he works on a longboat on the Salween River. On the nearby Thailand-Burma (Myanmar) border, the Burmese-Karen conflict, the world's longest-running civil war, rages into its 60th year. But Rambo, who lives a solitary life in the jungle-covered mountains, fishing and catching poisonous snakes to sell, has long given up fighting, even as medics, rebels and refugees pass by on their way through the war-torn region.

That all changes when a group of missionaries search out the "American river guide." When Sarah (JULIE BENZ) and Michael Bennett (PAUL SCHULZE) approach Rambo, they explain that since last year's trek to the refugee camps, the Burmese military has laid landmines along the trails, making it too dangerous for overland travel. They ask him to guide them up the Salween River and drop them off, so they can deliver medical supplies, food and bibles to the persecuted Karen hilltribe people. After initially refusing to cross into Burma, Rambo agrees to take them, dropping off Sarah, Michael and the other aid workers at a predetermined site.

Less than two weeks later, pastor Arthur Marsh (KEN HOWARD) finds Rambo and tells him the missionaries did not return. He's mortgaged his home and raised money from his church’s congregation to hire a group of mercenaries (GRAHAM McTAVISH, MATTHEW MARSDEN, TIM KANG, REY GALLEGOS, JAKE LA BOTZ) to bring them back. Rambo asks if the missionaries are alive, and Marsh replies they were seen being held captive in a Burmese army camp. While Rambo's reluctance for violence and conflict are palpable, he knows he has to help and agrees to take the mercenaries up river into the ravaged war zone. What follows is a descent into hell on earth.

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