John Rambo, a Vietnam veteran, has survived many traumatic experiences in his life and has since retired to Thailand, where he spends his time hunting snakes for local entertainers and chauffeuring locals on his old PT boat.
Despite his best efforts to stay out of danger, a group of Christian human rights missionaries led by Michael Burnett and Sarah Miller approaches Rambo with the request to rent his boat in order to journey up the river to Burma. Burma has been a combat zone for nearly fifty years.
The Karen people of the region, who are primarily peasants and farmers, have been subjected to brutally repressive governance by the Burmese military and have struggled for survival on a daily basis.
Rambo accepts the offer after some internal deliberation and leads Michael, Sarah, and the other missionaries up the river. When the missionaries arrive in Karen village, they are caught up in a raid by the sadistic Major Pa Tee Tint and a group of Burmese army troops.
Tint and his men torture and murder a section of the villagers and missionaries, while the others are held captive. Concerned about their absence, the mission's minister rallies a crew of mercenaries and asks Rambo to take them on his boat because he knows their exact location. But Rambo can't stay behind: he joins the crew to free the survivors from Major Tint's hands in what could be one of his most dangerous missions ever.