"Dorohedoro" is set in a grim, chaotic world divided into two realms: the dystopian, polluted Hole and the magical, orderly Sorcerer's World. The narrative centers on Caiman, a reptilian-headed amnesiac who seeks to uncover his true identity and the cause of his transformation. Caiman is aided by his friend Nikaido, a skilled martial artist and restaurant owner, as well as a group of eccentric allies. Together, they hunt sorcerers, who use humans in the Hole as test subjects for their magic.

The story intertwines with the lives of sorcerers from the Sorcerer's World, particularly En, a powerful crime boss and leader of the En Family. En's subordinates, including the enigmatic Shin and the chaotic Noi, are tasked with eliminating threats to their organization. As Caiman and Nikaido investigate the sorcerers, they cross paths with En's faction, leading to violent confrontations and unexpected alliances. The plot delves into the origins of magic, the nature of identity, and the moral ambiguity of both humans and sorcerers.

Key characters include Ebisu, a sorcerer with a childlike demeanor and a penchant for experimentation; Fujita, a nervous sorcerer struggling with his loyalty to En; and Risu, a former sorcerer turned resistance fighter. The series explores themes of survival, loyalty, and the blurred lines between good and evil, all set against a backdrop of dark humor and visceral action. The narrative is nonlinear, with flashbacks and shifting perspectives that gradually reveal the interconnected fates of the characters and the mysteries of their world.