The events of the game take place in 2102 (2103 in the supplements) in West Virginia. The player is a resident of Sanctuary 76 (The Resident) who has slept his way to the surface. Finding the Sanctuary Caretaker's holoscripts, who left it before anyone else, the player realizes that the region is in danger in the form of the burned-people infected with the infection, which over time turn into motionless statues that, as they decay, spread the disease, infecting other creatures as well as humans. As it turns out, the source of that disease is the beast-eaters. They are mutated dragon-like bats that live underground. As the story progresses and quests are completed, the player creates a vaccine against the plague of St. John's Bats.
Next, the Resident must infiltrate the well-hidden bunker of the Enclave, the former U.S. government. There he encounters MODUS, the supercomputer that killed all members of the Anclave as revenge for trying to destroy it. MODUS tells him about nuclear missiles and how to launch them. The player takes possession of the launch codes and, after bombarding the main rift where the beastmen come out, encounters an even more terrifying threat: the beastmen's womb. He manages to kill her in a fierce battle, and the beastmen, left headless, scatter like ants without a queen.
