Twenty-five years after the Great War, Vault 76 is opened up and its residents given the task of repopulating the Wasteland. Shortly after they emerge from the Vault, the player character is contacted by the Vault Overseer. She reveals that Vault 76 was given a secret mandate to secure an arsenal of nuclear weapons deployed throughout Appalachia in three still-functioning nuclear missile silos: Site Alpha, Site Bravo, and Site Charlie. The player character is directed to contact the Responders, a faction of emergency services personnel who tried to aid the residents of Appalachia during the war; however, they discover that the Responders evacuated after they came under attack from the Scorched. Further investigation reveals that the Scorched are human beings infected by the "Scorched Plague", and are led by the Scorchbeasts; massive mutated bats that came into contact with an Enclave bioweapon kept in an old mining facility, causing exponential growth and a symbiotic control over the plague that created them.
Players may play individually or with a party of up to three others. The servers for the game are public dedicated servers, with the player automatically allocated to one of them. While the game was expected to launch with public servers only, executive producer Todd Howard revealed plans for private servers to be introduced some time after the game's launch. These private servers allow players to invite friends and to prevent undesirable aspects of player versus player gameplay such as griefing from affecting an individual player's experience of the game.