Lucy and the Ghoul hear a woman scream from an abandoned hospital. Against the Ghoul's wishes, Lucy ventures in to investigate, with the two discovering a wounded man and woman. Radscorpions begin to attack the group, with the woman and the Ghoul both stung. Lucy uses her last stimpak on the woman instead of the Ghoul because of his cruelty shown to her, telling him that she will return for him once she returns the woman to her home. After rescuing the woman, the woman leads Lucy back to a Legion camp to be captured.
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.