Keisuke Amano, Natsume's brother who doesn't believe in supernatural phenomena. But as he notices his sister is frequently comes back home late, he decided to stalk her, only to find out she is exorcising evil Yo-kai and running a Yo-kai detective agency. With their secret revealed to him, Natsume decided to let him tag along in her activities as they investigate Yo-kai crimes and take on evil Yo-kai to maintain peace all over the city.

There used to be a boy who could control Yo-kai with a mysterious watch. However, he became unable to see Yo-kai when he became an adult. With the boy's duties finished, the watch was buried away in space-time. Then 30 years later, quiet everyday life comes to an end as a fateful day beging with a comet drawing near. The terrible Yo-kai virus Onimaro infects people's malevolent intentions and spreads infinitely. The one chosen by the Yo-kai Watch is the one who can save humanity from its crisis. The bond between humans and Yo-kai may be recovered with the attainment of a new Yo-kai Watch.