Lucy MacLean and the Ghoulhug a group of Great Khans in Novac while tracking Lucy's father, Hank. They follow his tracks into the abandoned Vault 24, where they discover a Vault-Tec experiment that attempted to brainwash Americans into becoming communists through the use of the implanted chips. The only living person in the vault creepily tells Lucy to go home before his head explodes due to the chip.
It is the aftermath of the Great War of 2077, an apocalyptic nuclear exchange between the United States and China in an alternate history of Earth where advances in nuclear technology after WWII led to the emergence of a retrofuturistic society and a subsequent resource war. Many survivors took refuge in fallout bunkers known as Vaults, most being unaware that each Vault was designed to perform sociological and psychological experiments on the Vault Dwellers on behalf of Vault-Tec. More than 200 years later in 2296, a young woman named Lucy leaves behind her home in Vault 33 to venture out into the dangerously unforgiving wasteland of a devastated Los Angeles to look for her father, who has been kidnapped by wasteland raiders. Along the way, she meets a Brotherhood of Steel squire and a legendary ghoul bounty hunter, each having their own mysterious pasts and agendas to settle.