The protagonist, the "Ark Survivor", emerges into this setting in year 2135, 106 years after being put into stasis inside an underground shelter called an Ark. These underground shelters are the direct result of the Eden Project, a massive international undertaking in which hundreds of Arks, containing cryogenic pods, were sealed under the surface of the Earth in order to preserve enough of the human population to rebuild civilization in the future. The Eden Project, however, was far less successful than hoped. The Ark Survivor's Ark in particular is heavily damaged, with all of its other residents dead, and equipment destroyed as well, and so he wakes up alone and uninformed. With no memory of his identity or objective, the Ark Survivor is forced to head for the surface.
When the Survivor reaches the surface, he is attacked by members of the ghost clan. Dan Hagar (played by John Goodman), a wasteland settler, saves him and brings him to his settlement. Dan informs the Ark Survivor that The Authority, a hostile faction, is looking for him and other Ark survivors for an unknown purpose. The Ark Survivor helps Dan's settlement and the Outrigger settlements by completing a few easy jobs. During this time, it is revealed that the nanotrites injected into the Ark Survivor's blood before he was sent into hibernation have granted him superhuman abilities to help him survive the harsh environment. However, it is these nanites that make him valuable to the Authority. Because his presence is too dangerous for the settlement, the playerleaves and goes to the nearby town of Wellspring.
During his stay in Wellspring, the Survivor helps the town with various problems such as fighting off bandits and mutants and ferrying supplies. Eventually, he comes into contact with Dr. Kvasir, an elderly scientist who used to work for the Authority. Kvasir tells the Ark Survivor about the inhumane experiments the Authority was responsible for, such as the creation of the mutants. Kvasir puts the Ark Survivor into contact with the Resistance, an anti-Authority group. After rescuing their leader, Captain Marshall, the Ark Survivor begins attracting attention from the Authority, forcing him to flee Wellspring and then join the Resistance at their headquarters in Subway Town. Like he did for Wellspring, the Ark Survivor earns the trust and gratitude of the citizens of Subway Town by assisting them with various problems. The Ark Survivor also learns what had happened in the past century from Marshall, who is an Ark survivor himself. Shortly before Apophis struck, one of the generals in charge of the Ark project sabotaged the operation by ensuring that only the Arks with people loyal to him would be opened, leaving the rest to stay underground in hibernation. These Ark survivors would eventually form the Authority.
With the Authority beginning to forcefully expand its influence on the Wasteland settlements, the Resistance is forced to act. With the help of the Ark Survivor, they are able to recover data that shows the location of every Ark on the planet. Marshall plans to use this data to activate all the Arks and form an army that can defeat the Authority. However, the only way to do this is to transmit the data from Capital Prime, the main headquarters for the Authority. Alone, the Ark Survivor fights his way through Capital Prime and manages to transmit the Arkactivation code. The game then ends as all of the remaining Arks simultaneously activate and surface.