Episode One The game begins with the narrator reading the first verse of a poem, later called The Quartet for the Dusk of Man. The player then designs a character of their choosing; with an introduction in the 1920s suburban neighborhood of the Player. A mysterious voice instructs the Player, whose home is quickly destroyed by a giant robot (a steampunk version of Fruit Fucker Prime), while smaller steampunk Fruit Fuckers attack. After a brief tutorial, the player teams up with Tycho Brahe, a scholar of Apocalyptic Studies turned detective, and his exceedingly violent partner who fought with the devil, Johnathan Gabriel, in search of information on Fruit Fucker Prime.

Episode Two Several months after Episode One ended, the Player has rebuilt his/her house (a tent), and Tycho and Gabe have set out to destroy Fruit Fuckers and try to find a lead on Fruit Fucker Prime. While escaping from a swarm of them, they crash a truck into the Player's (partially rebuilt) house, and recruit him/her to help them track down their lead. A trip to Anne-Claire's reveals that they have found the original designer of the Fruit Fuckers: Dr. Jonathan Crazoir, presently incarcerated in the same sanatorium as Tycho's father and grandfather when they succumbed to the insanity inherent to dealing with otherworldy affairs. She also demands they collect various pieces of equipment for one of her experiments: Five bolts of silk thread, preferably spider silk, a golden bolt, a truck or tractor engine, and a molecule of Energite, a highly unstable element. They enter the sanitarium to find Crazoir, who promises to give Tycho, Gabe, and the Player everything related to his research, as well as a "robot monkey card", if they can free him from the madhouse. After wooing the receptionist, they encounter huntsman/sanatorium owner Dr. Wolfington, who has used the millions made from the Brahe family's inevitable descent into madness to hunt down and kill every rare animal in the world. He declares the Player, Tycho, and Gabe all unfit for society after a rigged ink blot test, and has them injected with various chemicals to induce insanity.

Episode 3 The main game begins with Tycho receiving a phone call which is described as 10 minutes of silence, prompting Tycho and Gabe to go to the Arcadia boardwalk where they had previously defeated the mime god and members of his cult. Teaming up with Anne-Claire, they fight past the cultists, and eventually face off against a crabomancer, then, upon defeating it, recover pins which bestow classes on whomever wears one (similar to the job system in early Final Fantasy games). They return to their office, only to find that Dr. Blood has orchestrated the theft of the Necrowombicon. Anne-Claire returns home, Tycho and Gabe team up with Jim, a former colleague who lost his body in a work-related incident, reducing him to a skull floating in a jar of green liquid. Jim is unable to speak, but can follow Tycho and Gabe, as well as participate in combat. Following leads, they arrive at the museum of contemporary and ancient works, where Tycho is reunited with Moira, his ex-wife, who joins the party. When asked if they can re-recruit Anne-Claire, Tycho answers she is on vacation with her parents. The party discovers that a painting has been stolen from the museum, the painting being one of four representing the god of doors, Yog-Modaign, a death-god like figure.

Episode 4 The fourth episode begins with Gabe and Dr. Blood crashing down onto a hellscape. Without other options, Gabe is forced to pair with Dr. Blood, who gleefully explains that when they defeated Yog Modaign, the apocalypse happened and the world was destroyed. Those closest to the epicenter were tossed into a dimension called Underhell, so-called because it resembles a massive floating continent, directly below the massive floating continent of Hell. Gabe reasons that Jim, Moira and Tycho must have been sent to Underhell as well and bargains with Dr. Blood to aid him in searching for them. Dr. Blood reveals his motivations: in his youth, he traded the soul of his lover Hestia for knowledge. He since had come to regret his actions, and engineered a premature apocalypse in order to send himself to Underhell, where he hoped to reunite with Hestia. Dr. Blood also informs Gabe that since they are not of the same make-up as Underhell, they cannot harm its inhabitants, meaning they must use Underhell monsters to fight for them (similar to Pokémon). They head towards a large pillar structure where Dr. Blood believes he will find Hestia.