Mary Smith is a clumsy girl with wild red hair who can't seem to do anything right. After moving in with her Great Aunt Charlotte, Mary finds herself lonely and bored, until one day she spies a cat which seems to keep changing color every time she sees it. Curiosity gets the better of her and she follows it into nearby woods. Deep in the forest, the cat takes her to a clearing with dead trees and brown grass, where the only sign of life is a cluster of mysterious blue flowers that Mary has never seen before. The gardener of the estate later tells her that the rare species is called Fly-by-Night, and is said to be sought by witches for its incredible magical power. When the strange cat returns to her one night, Mary is led once again into the woods, but this time to an old broomstick hidden by a gnarled tree. After she clumsily squashes some Fly-by-Night against the broomstick, it begins to glow, whisking her off into the sky. Her wayward journey ends at the Endor College for Witches, where she is mistaken for a new student. And so, Mary must learn to look after herself in this marvelous new world of magic, where things are not always as they seem.

In the year 2041, World War III has wiped out two-thirds of the human population, and in the newfound structure, the belief in any god or beyond-human entity is considered a preposterous notion. In order to prevent citizens from bearing possibly incriminating thoughts, the government has assembled a Special Weapon Enforcement division to capture and rehabilitate such believers. The Kirihara brothers, Naoya and Naoto—who were hidden away from society by their captors for years to conceal their psychic abilities—were promised freedom once the world was ready to face their existence. Now, wandering in the appalling new societal climate where psychics are not welcome, the brothers find themselves on the run from the Enforcement's devoted operatives, Yuuya and Takuya Kuroki.

Rikuo Nura, a part-youkai and part-human boy, grew up as the young master of the Nura Clan. While he treated the clan, which consists of youkai of all shapes and sizes, like family, he soon learned that he was the only one among his classmates who saw youkai in this light. To most, they were terrifying creatures of folklore who ate children and relished in bloodshed. Taking this to heart, he swore to live his life as a normal human. Normalcy, however, is hard to come by for young Rikuo. Complicating his goal are his youkai attendant, who under the name Tsurara Oikawa, goes to school alongside him; the young onmyouji Yura Keikain; and his close friend Kiyotsugu, who idolizes youkai and hopes to prove their existence. To make matters worse, rival youkai and other entities threaten to harm those Rikuo holds dear. If he wants to protect what's important to him, Rikuo must acknowledge his ancestry—that he is the grandson of the legendary Nurarihyon—and transform at night into a youkai, becoming worthy of being the next leader of the Nura Clan.

Dismissed as a hopeless loser by those around him, 27-year-old Arata Kaizaki bounces around from one job to another after quitting his first company. His unremarkable existence takes a sharp turn when he meets Ryou Yoake, a member of the ReLife Research Institute, who offers Arata the opportunity to change his life for the better with the help of a mysterious pill. Taking it without a second thought, Arata awakens the next day to find that his appearance has reverted to that of a 17-year-old. Arata soon learns that he is now the subject of a unique experiment and must attend high school as a transfer student for one year. Though he initially believes it will be a cinch due to his superior life experience, Arata is proven horribly wrong on his first day: he flunks all his tests, is completely out of shape, and can't keep up with the new school policies that have cropped up in the last 10 years. Furthermore, Ryou has been assigned to observe him, bringing Arata endless annoyance. ReLIFE follows Arata's struggle to adjust to his hectic new lifestyle and avoid repeating his past mistakes, all while slowly discovering more about his fellow classmates.