Academy City, Japan, is at the forefront of science. Besides being 30 years ahead of the world technologically, more than three-fourths of this peculiar city's population consists of students developing their psychic abilities as espers in various institutions. Among these students is Touma Kamijou, a high school boy with the lowest psychic rank of zero, but with a mysterious power no scientist can understand: Imagine Breaker, which allows him to negate other supernatural abilities. This, however, doesn't affect Kamijou's life in the least as he plays his role as a regular teenager; that is, until he meets the strange Index Librorum Prohibitorum, a young girl who has memorized the entirety of the forbidden grimoires, and now a dangerous organization is hunting Index down. With several magicians looking to harm the girl, Kamijou will defend his new companion at all costs as he discovers a strange new realm of the supernatural.

Sentenced to death, ninja Gabimaru the Hollow finds himself apathetic. After leading a blood-soaked life, Gabimaru believes he deserves to die. However, every attempt to execute him inexplicably fails. Finally, Sagiri Yamada Asaemon, a fledgling member of a famed executioner clan, is asked to take Gabimaru's life; yet Sagiri makes no move to kill him as requested. Insisting that Gabimaru will not die because of his love for his wife, Sagiri instead offers him the chance to obtain a full pardon for his crimes. If he can travel to the island of Shinsekyo and obtain the Elixir of Life—which supposedly grants immortality—and bring it back for the shogun, then his freedom will be assured. But of the many who have traveled to Shinsekyo in search of the mythical Elixir, not a single person has returned sound of mind, if at all. Though unaware of the numerous dangers ahead, Gabimaru decides to accept the offer—alongside ten other death row convicts—in hope that he and his wife may finally live in peace.

Reeling from her recent breakup, Momo Ayase, a popular high schooler, shows kindness to her socially awkward schoolmate, Ken Takakura, by standing up to his bullies. Ken misunderstands her intentions, believing he has made a new friend who shares his obsession with aliens and UFOs. However, Momo's own eccentric occult beliefs lie in the supernatural realm; she thinks aliens do not exist. A rivalry quickly brews as each becomes determined to prove the other wrong. Despite their initial clash over their opposing beliefs, Momo and Ken form an unexpected but intimate friendship, a bond forged in a series of supernatural battles and bizarre encounters with urban legends and paranormal entities. As both develop unique superhuman abilities, they learn to supplement each other's weaknesses, leading them to wonder if their newfound partnership may be about more than just survival.

Kings are individuals who have been bestowed with incredible supernatural powers and granted the ability to recruit others into their clans. Protecting the lives and honor of their clansmen is an integral part of the Kings' duties. After a video depicting the heinous murder of a Red Clansman spreads virally, the unassuming student Yashiro Isana is accused of homicide. Now, a manhunt is underway for his head, bringing him into contact with the infamous Black Dog Kurou Yatogami—a skilled swordsman and martial artist determined to follow the wishes of his late master, the Seventh King. Meanwhile, the current Red King, Mikoto Suou, faces his own imminent demise as the search for Yashiro narrows. But during Yashiro's struggle to prove his innocence, a greater conspiracy is unraveling behind the scenes; clouds begin to appear in his memory, and close friends start to question his very existence. What began as a simple murder is now leading towards a full blown war between Kings with the very fate of the world at stake.