After learning that he has only a year to live due to Werner syndrome-like symptoms, Snake is tasked by Campbell, now working with the United Nations Security Council, to assassinate Liquid Ocelot. In a Middle-Eastern war zone occupied by one of Liquid's PMCs, Snake meets Drebin, an arms dealer who injects Snake with nanomachines to use the latest weaponry, and Meryl. Snake reaches Liquid, but the latter transmits a signal that incapacitates those nearby with nanomachines. Snake sees Dr. Naomi Hunter, who departs with Liquid.

In South America, Snake locates Naomi, herself a captive of Liquid. She explains that Liquid plans to use the biometrics of Big Boss to access and take command of the Patriots' firearms control system. Snake learns his accelerated aging is due to intentional genetic mutations as a human clone, and that the FOXDIE virus inside him will also mutate within months, spreading to the general populace and causing a deadly pandemic. Liquid's PMC soldiers kidnap Naomi, but Snake rescues her, assisted by Drebin and Raiden, and they escape, though Raiden is injured by Vamp.

Snake locates an Eastern-European resistance group, which happens to possess the comatose body of Big Boss, in order to heal Raiden. Its leader EVA reveals she was the surrogate mother to Snake and Liquid through the cloning process. They move Big Boss' body by boat while Liquid's PMC soldiers attack decoys. Liquid captures the body and obtains the biometrics, intending to infiltrate the Patriots' system by using the repaired artificial intelligence (AI) core, GW, as a trojan. U.S. soldiers arrive to arrest Liquid, but he kills them after disabling their firearms. Big Boss' body is incinerated, and Snake saves EVA from the fire when she tries to save the body, but both are badly injured in the process. Naomi leaves with Liquid, but Otacon tracks them. EVA dies from her injuries.