Mononoke follows a wandering, nameless character known only as the "Medicine Seller" (voiced by Takahiro Sakurai). The series is made up of individual chapters in which the medicine seller encounters, combats and subsequently destroys mononoke. The "mononoke" are a type of ayakashi, unnatural spirits that linger in the human world.

The Medicine Seller always proceeds in the same manner, using his knowledge of the supernatural to fend off the mononoke until he can learn the spirit's shape (Katachi), truth (Makoto) and reasoning (Kotowari). Only then can he unsheathe his sword and exorcise the demon.

The English subtitles translate these three necessities as Form, Truth, and Reason.

The opening track is "Kagen no Tsuki" by Komatsu Ryouta and Charlie Kousei and the ending is "Natsu no Hana" by JUJU.