The film opens with newsreels of the crisis in Burma. Burma (officially known as Myanmar) is under the iron fist rule of Than Shwe and takes harsher stances against the nation's pro-democracy movement. Rebels are thrown into a mine-infested marsh and then gunned down by the Myanmar Armed Forces, while the cigarette-smoking Burmese military officer Major Pa Tee Tint gazes grimly at the scene.

Former U.S. soldier John Rambo still lives in Thailand and now resides in a village near the Burmese border. He makes a living capturing venomous snakes and selling them in a nearby village. He also transports roamers in his boat. A missionary, Michael Burnett (Paul Schulze), asks Rambo to take him and his associates up the Salween River to Burma on a humanitarian mission. Rambo refuses, revealing himself to be bitter and cynical, but is convinced by Sarah Miller (Julie Benz) to take them.

The boat is stopped by pirates who demand Sarah in exchange for passage. After negotiation fails, Rambo kills them all. Although his actions save the missionaries, it greatly disturbs them. Upon arrival, Michael says that they will travel by road and will not need Rambo's help for the return trip. The mission goes well until the army, led by the Major Tint, brutally attacks the village, killing most of the villagers, sometimes after frightful torture and mutilation, and two missionaries, and kidnapping the rest. When the missionaries fail to come back after ten days, their pastor comes to Rambo to ask for his help in guiding hired mercenaries to the village where the missionaries were last seen.

Troubled by the small platoon (which includes a child), Rambo decides to accompany the soldiers, following them from behind. They come to the destroyed village filled with mutilated humans and animals, and hide when Myanmar soldiers arrive in a truck with villagers. As the soldiers are about to massacre the villagers, Rambo appears and shoots them all with a bow and arrows. Hijacking the soldiers' truck, they create a plan to save the hostages at the P.O.W. camp, doing so within fifteen minutes to avoid alerting the army. Rambo helps Sarah and the others to escape. The Myanmar Army (Tatmadaw) unit finds their hostages missing and organizes a massive manhunt. Everyone except for Rambo, Sarah, and "School Boy" is captured. Sarah and the School Boy hide in the trees while Rambo sets off a claymore mine in the jungle, causing an explosion that levels a large area and kills several soldiers. Meanwhile Sarah and the School Boy have found the others being brutally beaten by Tint. Just as the group is to be executed, Rambo appears, hijacks a truck-mounted .50-caliber machine gun and engages the Burmese army. Seeing this, Schoolboy begins shooting, and, as several of the soldiers are killed the mercenaries take their weapons and begin to fight back. After several missionary deaths a group of Karen rebels joins the fight to help Rambo and the mercenaries defeat the Burmese army. Michael, the previous pacifist, jumps a soldier and beats him to death with a small rock. Seeing that the battle is lost Major Tint decides to flee, only to run into Rambo's machete, who then proceeds to disembowel him.

Encouraged by Sarah's words, Rambo returns to the United States. The last scene shows him walking along a rural highway, past a horse farm and a rusted mailbox with the name "R. Rambo" on it (earlier, Rambo said that the only family he had might be his father). He makes his way down the gravel driveway as the credits roll.




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