Four years after the events of the San Hieronymo incident, Big Boss—who prefers his original codename, Snake—and Kaz Miller have established Militaires Sans Frontières, a small mercenary faction, on the Colombian coast. They are approached by Ramon Galvez Mena, a professor at the University of Peace, and his student, Paz Ortega Andrade. Galvez attempts to hire MSF to investigate an army that has discreetly occupied parts of Costa Rica. Snake refuses, identifying Galvez as a KGB agent, but is convinced when Paz plays a recording of The Boss.

When Snake arrives in Costa Rica, he begins to suspect that the mystery army has brought nuclear weapons with them. Enlisting the help of the Sandinista Liberation Army, he tracks a shipment to a research facility deep in the mountains. His suspicions are confirmed when he witnesses Hot Coldman, a senior CIA agent, announce his intentions to fire a live nuclear weapon as part of a project code-named "Peace Walker", a fail-deadly nuclear tank. Snake reveals himself to Huey Emmerich, one of Peace Walker's designers, who agrees to help him stop Coldman.