Following a bad experience teaching at a public high school that resulted in a break from working, Haruaki Abe eagerly takes up a new job at Hyakki Academy. Despite his cowardice, the novice teacher is motivated to do better this time around. However, his mind quickly changes when he finds out that everyone at the school is actually a supernatural being known as a youkai, leaving him glaringly out of place as the only human around. Facing his class as its new homeroom teacher, Abe immediately becomes a target for the students' antics due to his quick-to-scare nature. Though as the man starts to learn more about the creatures, as well as himself, getting along with the unruly group might not be as hard as he originally thought as their school lives begin to get more vibrant.

After witnessing his mother's death at a young age, Uryuu Kamihate grew up disillusioned with the gods, dismissing faith in them as utter nonsense. Due to his beliefs, he aims to become a doctor, spending most of his time studying to enter the prestigious Kyoto University. To further his studies, Uryuu searches for a new place to take him in and get away from the noisy environment of the orphanage where he grew up. Chidori Amagami, head priest of the Amagami Shrine, allows him to stay at the Amagami residence. However, Uryuu has to live there with Chidori's three granddaughters—Yae, Yuna, and Asahi—who serve as shrine maidens. Moreover, Chidori has another condition for Uryuu: he has to marry one of the sisters to ensure the shrine's future and one day inherit it. But with Uryuu's goals and outlook naturally clashing against the sisters' beliefs, this already daunting ordeal seems outright impossible.

Having resolved the crisis in the Petrification Kingdom, Senkuu and his companions gear up to deal directly with the mastermind behind the petrification phenomenon—who supposedly resides on the moon. The ambitious spaceship project, however, requires immense manpower and critical resources scattered across the world. Thus, the Kingdom of Science exploration team kick-starts its transcontinental journey on the ship Perseus to gather them all. Equipped with modern technology and bolstered by the new, capable members in their ranks, the exploration team feels confident about setting sail to their first destination: America. They soon realize that the region now hosts adversaries controlling the resources they need, doing so with scientific technology which rivals and even exceeds their own. In a battle of science versus science, Senkuu and his team must outsmart their rivals if they are to have any chance of ensuring the continued survival and rejuvenation of humanity.