On October 23, 2077, at a birthday party in Los Angeles, actor Cooper Howard entertains the children with his cowboy tricks, while the adults are distracted by news report regarding a possible nuclear threat. As the kids go inside for cake, Howard converses with his daughter Janey over his reluctance in raising his thumb for a photograph based on his experiences as a Marine. Suddenly a nuclear bomb hits the city, sending a shockwave towards the house. The attack causes pandemonium and the partygoers flee, with some trying to enter a fallout shelter. Howard takes his daughter and flees on horseback while more bombs hit the city, as Earth experiences a nuclear holocaust.




219 years later, groups of humanity have been living in underground colonies known as "Vaults", built to preserve American society in the event of nuclear war. A young woman, Lucy MacLean, is a Vault Dweller from Vault 33, helping the community in many ways. Wanting to get married, she convinces a special council to grant her a wedding with a man from nearby Vault 32. After the wedding, Lucy and her new husband Monty consummate their marriage. Meanwhile, Lucy's younger brother Norm becomes suspicious of the visitors from Vault 32 and investigates the empty Vault. He discovers that Vault 32 has been destroyed and finds the mutilated corpse of a Vault Dweller.




Shortly afterwards, the visitors from Vault 32 begin to murder Vault 33 residents. Detecting high levels of radiation from her Pip-Boy, Lucy realizes that the visitors are not from Vault 32 but are actually raiders from the surface. Monty becomes aggressive and brutally attacks Lucy, stabbing her in the abdomen. Despite her severe injury, she manages to strike him back, slicing his face and throat with broken glass. After injecting herself with a Stimpak, Lucy rushes to the main reception area to find the raiders viciously attacking the Vault. Monty ambushes her, but her father Hank, the Overseer of Vault 33, attacks him from behind and drowns him. They run into Lee Moldaver, the leader of the raiders. Threatening Lucy's life, as well as several other Vault Dwellers, Moldaver drugs Hank and takes him to the surface. In the aftermath, Lucy resolves to find her father, and leaves Vault 33 with the help of Norm and their cousin Chet. She is astonished upon discovering the devastated remains of Los Angeles.




On the outskirts of Los Angeles, the Brotherhood of Steel, an organization dedicated to securing pre-War technology, trains young men in a boot camp. An aspirant, Maximus, is jealous when his friend Dane is selected to become a squire. However, Dane is forced to step aside when they are severely injured in the leg by a hidden razor blade. Maximus is suspected of having sabotaged Dane's injury, something that he admits he considered, but the Brotherhood chooses not to punish him when he professes a willingness to accept his fate. Maximus is named as the new squire and is assigned with his troop in pursuing a scientist from the Enclave who has escaped with dangerous technology.




Meanwhile, three bounty hunters sneak into a cemetery, to dig up and free a ghoul resembling Howard. The bounty hunters request his help in finding the Enclave scientist and offers to split his bounty. The Ghoul gleefully double-crosses them, and quickly kills all three men. He subsequently leaves to find the scientist himself.