Holo is a powerful wolf deity who is revered in the small town of Pasloe for blessing the annual harvest. Yet as years go by and the villagers become more self-sufficient, Holo has been reduced to a mere folktale. When a traveling merchant named Kraft Lawrence stops at the settlement, Holo offers to become his business partner if he takes her to her northern home of Yoitsu. The savvy trader recognizes Holo's unusual ability to evaluate a person's character and accepts her proposition. Now in the possession of both sharp bargaining skills and a charismatic negotiator, Lawrence inches closer to his goal of opening his own shop. However, as Lawrence travels the countryside with Holo in search of economic opportunities, he begins to realize that his aspirations are slowly morphing into something unexpected.

Ohana Matsumae is an energetic and wild teenager residing in Tokyo with her carefree single mother. Abruptly, her mother decides to run away with her new boyfriend from debt collectors, forcing the young girl to fend for herself—as per her mother's rely only on yourself philosophy—in rural Japan, where her cold grandmother runs a small inn. Driven to adapt to the tranquil lifestyle of the countryside, Ohana experiences and deals with the challenges of working as a maid, as well as meeting and making friends with enthralling people at her new school and the inn.

Once a hot springs inn, now a boarding house with extraordinarily cheap rent, Yuragi-sou is virtually uninhabited save for a few peculiar residents. As rumor has it, it is haunted by a vile ghost which scares away all potential tenants. Therefore, it is the perfect refuge for Fuyuzora Kogarashi—a broke, homeless psychic seeking an affordable roof to stay under and ghosts to exorcise. Kogarashi prepares for a face-off against the ghost, only to find out it is not as malicious as the rumors made it out to be. Instead, it is the ghost of a beautiful, silver-haired girl whose only recollection of her life before death is her name: Yuuna. Even more baffling is that the other tenants of Yuragi-sou not only are able to see Yuuna as well, but each has their own supernatural ability. Amidst the chaos caused by his quirky fellow residents, Kogarashi attempts to uncover the regret that keeps Yuuna anchored to the world of the living, lest she become an evil spirit sentenced to spend her afterlife in hell.

The Medicine Seller is a deadly and mysterious master of the occult who travels across feudal Japan in search of malevolent spirits called mononoke to slay. When he locates one of these spirits, he cannot simply kill it; he must first learn its Form, its Truth, and its Reason in order to wield the mighty Exorcism Sword and fight against it. He must begin his strange exorcisms with intense psychological analysis and careful investigative work—an extremely dangerous step, as he must first confront and learn about the mononoke before he even has the means to defeat it. The Medicine Seller's journey leads him to an old-fashioned inn where Shino, a pregnant woman, has finally found a place to rest. The owner has reluctantly placed her in the last vacant room; however, as she settles in, it quickly becomes clear that the room is infested by a lethal band of mononoke, the Zashiki Warashi. With his hunter's intuition, the Medicine Seller begins his investigation to discover the Form, the Truth, and the Reason before the Zashiki Warashi can kill again.