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A known person called the Lone Wanderer , is a young inhabitant of Vault 101, a fallout shelter in the Washington D.C. area. The Vault has reportedly been sealed for 200 years, until his father, James opens the only door to the outside world and disappears without any explanation. The Vault Overseer believes that the player was involved in his father's escape, and sends the Vault's security force to arrest him. This leaves the him little choice but to also escape from the Vault, with the hope of locating his father and finding out why he left.

Abandoned to rust, decay, and creeping vegetation, monuments from before the Great War still stand amidst the ruins of Downtown DC: the Capitol Building, the Jefferson Memorial and the battered remains of the Washington Monument; this desolate area is known as the Capital Wasteland. A central hub of civilization in the ruins of the former capital is Rivet City, based in and around the remains of an aircraft carrier carried far inland and beached by a catastrophic tidal wave whose waters have long since receded. Other large settlements include the towns of Megaton, Canterbury Commons, Big Town, Arefu, Tenpenny Tower and Paradise Falls. Movement between towns is done on foot through the wastes. In the Metro area rubble blocks the streets, but one can use the Washington Metro tunnels. The Brotherhood of Steel community is stationed in the Citadel built in the ruins of the pre-War Pentagon. The mysterious Mr. Burke and his employer, Allistair Tenpenny, tried to sabotage and destroy the town of Megaton. But it is super mutants, who since emerging from their refuges have waged an unceasing war against humans to invade their territory, and the Enclave - the self-styled inheritors of the power of the United States government - under the leadership of their new President John Henry Eden and his ruthless second-in-command Colonel Augustus Autumn, who are the player's biggest foes in the game