The player is the Sole Surivor of Vault 111, who emerges 210 years to the day and time after the Great War. Prior to this, there is a brief period of gameplay during the pre-War era showing the player living with their spouse and child.

As revealed in the trailer on June 3, 2015, the setting takes place in Boston, Massachusetts. Famous local landmarks like the Paul Revere Monument, the USS Constitution, as well as the Massachusetts State House with its unique Golden Dome are included in the game world. Other notable present-day locations that make an appearance in the game are Scollay Square, Bunker Hill memorial, and Fenway Park, which is renamed Diamond City. The events of Fallout 4 occur in 2287; a decade after Fallout 3 and six years after Fallout: New Vegas.

Vault 111 is in the northwest corner of the game map. The Sole Survivor starts the post-war adventure wearing the Vault 111 jumpsuit. The trailer featured a player character carrying a laser musket, meeting the dog companion Dogmeat and starting on a road leading away from the camera, a motif seen in various previous Fallout installments.

Vault 111 is also near Sanctuary Hills, the residential area where the Sole Survivor lived before the war. This is most likely the first location that the player comes across after emerging from the Vault. The protagonist's household robot, Codsworth, still resides there. Sanctuary Hills is also one of the player-built settlement sites.

The setting also includes mountains, coastal regions, the outskirts of the city and the downtown Boston area. A large and still inhospitable nuclear blast site is to the southwest. The starting area in the northwest contains low level enemies and is relatively safe, but the enemies get progressively tougher towards the southeast area of the map.