Twenty years after the events in Afghanistan, amid the political protests of the crisis in Burma, ruthless military officer Major Pa Tee Tint leads an army of Tatmadaw soldiers to pillage small villages in a campaign of fear. He watches with indifference as innocent villagers are forced into mine-infested marshes and orders his men to abduct the teenage boys of the villages to be drafted into his army.
Former soldier John Rambo now lives in Thailand in a remote village near the Burmese border where he makes a living capturing and selling snakes as well as taxiing people up and down the Salween River in his boat. He is approached by missionary Michael Burnett who asks Rambo to ferry his group into Burma on a humanitarian mission to provide aid to Karen tribes people. Rambo refuses, claiming that without weapons, there will be no changes, but is eventually persuaded by missionary Sarah Miller to make the trip.
During their trip, the boat is stopped by Burmese pirates who demand Sarah in exchange for passage. After negotiations fail, Rambo shoots the pirates. Michael is greatly disturbed at Rambo’s actions; upon arriving in Burma, he says that the group will travel by road and will not need him for the return trip, and that he intends to report Rambo’s actions to the authorities. The mission goes well until the Tatmadaw, led by Major Tint, suddenly attack, slaughtering most of the villagers and two missionaries and kidnapping the rest, including Michael and Sarah. When the missionaries fail to return, their pastor asks Rambo to guide a team of five mercenaries to the village where the missionaries were last seen.
Rambo agrees and accompanies the mercenaries to the drop-off. He offers to help but is refused by the team’s leader Lewis, who demands he stay at the boat. As the mercenary team arrives at the village, they find it completely destroyed, filled with mutilated human and animal corpses. Shortly after, a squad of Tatmadaw soldiers show up with a group of hostages. The soldiers are playing a game, forcing prisoners to run through a rice paddy with landmines, and betting on the outcome. The team takes cover, reluctantly planning to let the hostages be killed in order to avoid provoking a response from a much larger group of soldiers. Having disregarded Rambo as a simple boatman, the mercenaries are shocked when he appears and single-handedly wipes out the entire squad of Tatmadaw soldiers with his bow and arrow, allowing the hostages to escape unscathed.
Rambo convinces the team to avenge the massacre and save the hostages at the P.O.W. camp. Rambo and the mercenaries infiltrate the camp and successfully locate and rescue Sarah and the other prisoners and flee with them. Tint quickly learns of the situation and musters his army to find them. Rambo manages to get rid of a pursuit team by making a booby trap from an unexploded Tallboy bomb from World War II. Ultimately, though, the Tatmadaw manage to capture everyone except for Rambo, Sarah, and the mercenary sniper School Boy. Just as the captured mercenaries and hostages are to be executed, Rambo hijacks a jeep-mounted machine gun and ignites an intense shootout. Tint hides as the firefight escalates and kills one of the missionaries.The Tatmadaw, having a large numerical advantage, come close to victory but the Karen rebels show up and join the fight, turning the tide of the battle. Tint, realizing his defeat, attempts to escape the area, but Rambo intercepts and disembowels him.
In the final scene, Rambo, encouraged by Sarah’s words, has returned to the United States, walking along an Arizona highway until he sees a horse farm and a rusted mailbox. Reading the name “R. Rambo,” Rambo smiles and walks down the gravel driveway as the credits roll.