The character would start the game as a prisoner; whether the character was wrongfully imprisoned or guilty was to be determined at character creation. The game would have started in a strange prison as it was attacked by an unnamed force. An explosion would knock the character unconscious, and the cell door would be open when he awakened. The player would then escape into the wasteland while being pursued by strange assailants. After leaving, the character would have the power to shape the destiny of the wasteland. His interactions with organizations such as the Brotherhood of Steel and the burgeoning New Californian Republic (with both of these factions participating in a prolonged war with one another) could bolster or destroy the organizations, influencing people associated with them and eventually decide the fate of the region, much as in the previous two Fallout games.

One of the more significant elements of the plot and back story of Van Buren was to be an ongoing war between the Brotherhood of Steel and the New California Republic. The player would be able to visit various prominent settlements and fortresses controlled by either of the factions and their actions there would influence the proceeding of the war. An example of the how the player's interactions could alter the flow of the conflict would be in the case of the settlement situated in the area around the Hoover Dam. Here the player could choose whether or not to aid the settlement and its people in a myriad of tasks, which would lead to this isolated frontier outpost eventually deciding the fate of the war. The game's ultimate plot line was planned so that the events in the beginning of the game would have been part of a scheme by a rogue New California Republic scientist, Dr. Victor Presper, to seize control of a U.S. orbital nuclear weapons platform dubbed B.O.M.B.-001 and use it to initiate a second nuclear holocaust, cleansing the world of all but his chosen few. In the end, the player would not be able to stop all of the missiles from launching, and his or her decisions on where the missiles would strike would ultimately have decided the future of the world.