High school science-whiz Makoto Mizuhara is working on his newest project in preparation for the school festival, alongside his best friend Nanami Jinnai. Nanami's brother and Makoto's lifelong rival, the unscrupulous student council president Katsuhiko Jinnai, is under scrutiny for mishandling the school festival planning and is convinced that Makoto is plotting to steal his position. One night, as Makoto and Nanami are taking a break with their teacher Masamichi Fujisawa, Jinnai sneaks into the science lab and sabotages Makoto's device, which suddenly opens a portal that flings all four of them into another world! Upon arrival, Makoto is immediately attacked by a horde of giant bug monsters. While running from them, he comes across Fujisawa and a girl named Rune Venus. After Fujisawa fights off the monsters, a group of dignitaries arrives, looking for Rune, their princess. They inform Makoto and Fujisawa that they are in a world called El-Hazard and take them back to the palace of Roshtaria, their kingdom. Though her advisors are suspicious of the newcomers, Rune decrees that they are to be treated as guests and quickly befriends Makoto. Unaware that Nanami and Jinnai are in this world as well, Makoto gets to work trying to figure out a way back to Earth.

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.