"Made in Abyss" is set in a world centered around the Abyss, a massive, enigmatic chasm filled with ancient relics and dangerous creatures. The Abyss is divided into layers, each with its own unique ecosystem and increasing levels of peril as one descends. The story begins in Orth, a town built around the edge of the Abyss, where Cave Raiders, known as Delvers, explore its depths to recover artifacts. The Abyss is governed by the "Curse of the Abyss," a mysterious phenomenon that causes physical and mental harm to those who ascend, with the severity escalating the deeper one goes.

The protagonist, Riko, is a young orphan and aspiring Cave Raider who lives in Orth. She dreams of following in the footsteps of her mother, Lyza, a legendary White Whistle Delver who disappeared in the Abyss years ago. Riko’s life changes when she discovers a humanoid robot boy named Reg in the upper layers of the Abyss. Reg possesses advanced technology, including a powerful extendable arm, but has no memory of his origins. Together, Riko and Reg form a bond and decide to venture into the Abyss to uncover its secrets and find Lyza, who Riko believes is waiting at the bottom.

As they descend, Riko and Reg encounter various challenges, including hostile creatures, treacherous environments, and other Delvers with their own agendas. They are joined by Nanachi, a former human transformed by the Abyss’s curse into a furry, rabbit-like creature known as a Hollow. Nanachi provides crucial knowledge about the Abyss and its dangers, having experienced its horrors firsthand. The trio faces moral dilemmas and harrowing situations, including encounters with Bondrewd, a morally ambiguous White Whistle Delver who conducts unethical experiments on humans and Hollows.

The narrative explores themes of curiosity, sacrifice, and the consequences of pursuing forbidden knowledge. The Abyss itself serves as both a physical and metaphorical journey, with each layer revealing new mysteries and escalating stakes. The story balances moments of wonder and discovery with darker, more unsettling elements, creating a tone that is both adventurous and grim. Riko’s determination, Reg’s loyalty, and Nanachi’s resilience drive the plot forward as they navigate the Abyss’s depths, uncovering its secrets while confronting their own limitations and fears.