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John Rambo, having been tried, convicted, and sentenced to time at hard labor, is working in a labor camp prison when he gets a visit from his former commander, Colonel Sam Trautman. Trautman offers Rambo the chance to be released from prison after the events of the first film and given full clemency, but on condition of him going into Vietnam to search for American POWs. Rambo meets Marshal Murdock, an American bureaucrat who is in charge of the operation and he tells Rambo that the American public is demanding knowledge about the POWs and they want a trained commando to go in and search for them. Rambo is briefed that he is only to photograph the POWs and not to rescue them, nor is he to engage any enemy soldiers. Rambo reluctantly agrees and he is then told that an agent of the American government will be there to receive him in the jungles of Vietnam.

Rambo parachutes into the Vietnamese jungles, but loses most of his equipment in the process and is left only with his knives, his bow, and arrows. He meets the agent, a local woman named Co-Bao who wants to go to the United States, and who arranges for her and Rambo to go upstream with a group of river pirates. Rambo comes to the camp, and in contradiction to his briefing, he finds American prisoners there and rescues one of them from a makeshift crucifixion. Later at the camp, a patrol discovers a dead sentry whom Rambo eliminated with a throwing knife. In response, a large patrol goes out into the jungles in search of the (unknown to them) intruder. Rambo, Co and the American POW escape with the pirates, but are attacked by a Vietnam People's Navy gunboat and are promptly betrayed by the pirates, who fear the military's reprisals should they not cooperate; Rambo sends Co and the POW to safety and manages to destroy the gunboat with an RPG-7 and kill all the pirates. When Rambo calls for extraction, he is denied as Murdock fears what will happen to him and his party if the American public come to know about it.

Rambo and the American POW are recaptured. Rambo's wrists are bound to an oxen yoke and he is lowered, exposed, into a leech-infested cesspool (or possibly a pit dug especially for the purpose of torture). Later Rambo learns that the Soviet Army is aiding the Vietnamese and training them, and is tortured badly by a Soviet officer, Lt. Col. Podovsky and his silent, robust henchman Sergeant Yushin. Rambo is ordered to contact the American military and tell them that they should not send any more commandos for rescue operations in Vietnam. Meanwhile, Co enters the camp in the guise of a ********* and comes to the hut in which Rambo is held captive. Rambo agrees to Podovsky's condition, but instead threatens Murdock on the radio that he is "coming to get you." He then escapes from captivity into a nearby jungle with Co's help. Co then tends to Rambo's wounds and begins to implore him to take her to the United States. Rambo agrees and they kiss; however, they are then attacked by some Vietnamese soldiers and Co is killed. Rambo kills them all (except for their commander, who escapes, but is later killed by one of Rambo's exploding arrows) and then buries Co's body in the jungle.

Following his escape, the camp's Soviet and Vietnamese soldiers are sent to look for him. Rambo assembles his weapons, and using guerrilla warfare tactics, is able to kill a large number of enemy troops. He proceeds to a small enemy camp and destroys it and several vehicles with explosive arrows. He hijacks a UH-1N Twin Huey helicopter from the Soviets after killing Sergeant Yushin and proceeds towards the POW camp. He destroys most of the camp with the helicopter, then lands and arms himself with the M60 machine gun that is mounted on the Huey, kills the remaining soldiers, and rescues all the POWs. They get to the helicopter and head towards the American camp in Thailand. Lt. Col. Podovsky chases them in his Mil Mi-24 helicopter gunship. Although Rambo's helicopter is heavily damaged by Podovsky's helicopter, he manages to land his helicopter on a river, then fakes his death. When Podovsky comes near him and gets careless, Rambo fires a LAW at Podovsky's chopper, obliterating it.

Rambo then returns to the base and wrecks Murdock's command center. He threatens Murdock with a knife, challenging him to find and rescue the remaining American POWs in Vietnam. Trautman then comforts Rambo and tries to pacify him. An angry Rambo responds that he only wants his country to love its soldiers as much as its soldiers love it. As Rambo leaves, Trautman asks him, "How will you live, John?" To which Rambo replies, "Day by day."