In a city so dismal it's known only as "the Hole," a clan of Sorcerers have been plucking people off the streets to use as guinea pigs for atrocious "experiments" in the black arts. In a dark alley, Nikaido found Caiman, a man with a reptile head and a bad case of amnesia. To undo the spell, they're hunting and killing the Sorcerers in the Hole, hoping that eventually they'll kill the right one. But when En, the head Sorcerer, gets word of a lizard-man slaughtering his people, he sends a crew of "cleaners" into the Hole, igniting a war between two worlds. Dorohedoro takes place in a post-apocalyptic setting, split in two separate dimensions; the Hole, a dismal cityscape where humans reside; and the Sorcerers' world, home of sorcerers. Despite appearing similar, humans and sorcerers are two distinct species, the former evolving naturally, while the latter was created by a primordial devil named Chidaruma. Sorcerers are capable of entering the Hole by summoning magical doors.