Main plot

For the first 19 years of their life from 2258 to 2277, the player character grows up within the isolated confines of Vault 101 (designed to never be opened as a social experiment by the pre-war corporation known as Vault-Tec) alongside their father James, a doctor and scientist who assists in the Vault's clinic. While growing up, their father comments about their deceased mother Catherine and her favorite passage from the Bible (Revelation 21:6), which speaks of "the waters of life." Upon reaching their 19th birthday, chaos erupts when James suddenly leaves the Vault, causing the Overseer to lock down the Vault and send security guards after James' child. Escaping from the Vault with the aid of the Overseer's daughter Amata, the search for James across the Wasteland begins at the nearby town of Megaton, named for the undetonated atomic bomb at the center of town, and eventually into the ruins of Washington, D.C., and the Galaxy News Radio station, whereupon James' child, after helping the station's enthusiastic DJ Three Dog, is given the moniker of The Lone Wanderer. Directed by Three Dog towards Rivet City, a derelict aircraft carrier serving as a fortified human settlement, the Lone Wanderer meets with Doctor Madison Li, a scientist who worked alongside James. Li informs the Lone Wanderer that their parents were not born in Vault 101, but lived outside of it, where they worked together upon a plan they conceived to purify all the water in the Tidal Basin and eventually the entire Potomac River, with a giant water purifier built in the Jefferson Memorial, called Project Purity. However, constant delays and Catherine's death during childbirth forced James to abandon the project and seek refuge in Vault 101, where he took the Lone Wanderer to raise within a safe environment far away from the dangers of the wasteland.

Learning that James seeks to revive the project and continue his work by acquiring a Garden of Eden Creation Kit (G.E.C.K.), a powerful piece of technology issued by Vault-Tec intended to assist in rebuilding civilization after the war, the Lone Wanderer tracks him down to Vault 112, and frees him from a virtual reality program being run by the Vault's sadistic Overseer, Dr. Stanislaus Braun, whom James had sought out for information on a G.E.C.K.. Reunited with their father, the pair return to Rivet City and recruit Li and the other project members to resume work at the Jefferson Memorial. As they begin testing the project, the Memorial is invaded by the Enclave, a powerful military organization formed from the remnants of the United States government, which continues to remain active despite the demise of their brethren on the West Coast thirty years previously. Seeking to stop them from gaining control of his work, James urges the Lone Wanderer to finish his work and find a G.E.C.K. before flooding the project's control room with massive amounts of radiation, preventing the Enclave's military leader, Colonel Augustus Autumn, from taking control of it and killing himself in the process. Autumn survives, however, and the rest of the team flees from the remaining Enclave soldiers. The Lone Wanderer, accompanied by the remaining Project Purity members, make contact with the Brotherhood of Steel within the ruins of the Pentagon, now known as the Citadel. With their help, the Lone Wanderer travels to Vault 87 to find a G.E.C.K., which had been used as a testing site for the Forced Evolutionary Virus (FEV) and now as a breeding ground for the Super Mutants. The Lone Wanderer recovers the G.E.C.K. from within the Vault with the optional help of a friendly Super Mutant named Fawkes. As they make their way out, the Wanderer is ambushed by Colonel Autumn and the Enclave and is captured with the G.E.C.K confiscated.