The story begins in 2077 in Sanctuary Hills, located near Concord, Massachusetts. The player character is at home with their spouse (Nate or Nora depending on the player character’s gender), their son Shaun, and Codsworth. A Vault-Tec representative admits the family into Vault 111, the local fallout shelter. Moments later, a news bulletin warns of an incoming nuclear attack. As the detonation occurs, the family evacuates to the Vault, where they are tricked into entering cryogenic tubes and frozen alive. After an unknown number of years, they are reawakened by two strangers, who murder the player’s spouse and kidnap Shaun. The player is put back into cryogenic sleep but awakens again when the life support system malfunctions. The player, now known as the “Sole Survivor” of Vault 111, vows to avenge their spouse’s death and find Shaun.
The Sole Survivor heads home to find Sanctuary Hills in ruins. They reunite with Codsworth, revealing that 210 years have passed since the war. Codsworth suggests that the Survivor goes to Concord for help. The Survivor finds and befriends Dogmeat, and assists the Minutemen faction in evacuating to Sanctuary Hills. The Sole Survivor then travels to Diamond City, a fortified settlement based in the ruins of Fenway Park, where they meet Piper. There, they learn about a secretive organization called the Institute that has been terrifying the Commonwealth by kidnapping people and replacing them with “synths”, synthetic humans indistinguishable from real humans.
With the help of Nick Valentine, the Sole Survivor uncovers the identity of their spouse’s killer: Conrad Kellogg (Keythe Farley). After learning from Kellogg that Shaun is being held in the Institute, the Sole Survivor kills him and retrieves a cybernetic implant from his brain to access his memories. During this time, the Brotherhood of Steel arrives in the Commonwealth on the Prydwen, an airship. The Sole Survivor learns from Brian Virgil (Matthew Waterson), an ex-Institute scientist, that teleportation is only way to enter the Institute. After the Survivor retrieves a chip and decodes it with the help of the Railroad, Virgil provides the blueprints for a teleportation device, which the Sole Survivor constructs by allying with the Brotherhood, Minutemen, or Railroad.
The Sole Survivor successfully enters the Institute and discovers that Shaun is the Institute’s director. Shaun, now an old man calling himself Father (Tony Amendola), reveals that he was kidnapped by Kellogg to become a specimen for synth experiments due to his pure pre-war DNA, and that the Sole Survivor remained in stasis for a further sixty years before being reawakened. He invites the Sole Survivor to join the Institute. If accepted, Shaun reveals that he is dying of cancer and wishes for the Survivor to become his successor. After initiating a purge in the Commonwealth, wiping out the Brotherhood and Railroad, the Survivor assumes control of the Institute after Shaun’s death. Otherwise, the Sole Survivor devises a plan with their faction to fight the Institute. Siding with the Brotherhood or Railroad will force the Sole Survivor to destroy the other faction. The Sole Survivor detonates a nuclear reactor, destroying the Institute. After this feat, if the Survivor sided with the Minutemen, they must lastly wipe out any remaining hostile faction. Otherwise, they will remain neutral.