A Certain Magical Index is set in a world where supernatural abilities are a reality. Individuals who possess special powers acquired via science are called Espers (超能力者 Chōnōryokusha).They possess their powers from birth, but most only awaken them during the Power Curriculum Program. Those Espers who awaken their abilities without the aid of special scientific instruments, whether at birth or through meditation, are referred to as Gemstones (原石 Genseki). Others, known as Magicians (魔術師 Majutsushi), gain their powers upon mastering the power of magic, either from obtaining knowledge from special books known as Grimoires (魔道書 Madōsho) or by using mystical artifacts, though the existence of magicians is a secret to the public. While Magicians align themselves with ancient religions, Espers are aligned with scientific institutions. This leads to a power struggle between the magic and science factions for control of the world.

The story is set in Academy City (学園都市 Gakuen Toshi), a technologically advanced city located in western Tokyo that is known for its educational and research institutions. Tōma Kamijō is a student in Academy City whose right hand, the Imagine Breaker, has

the ability to negate any supernatural power, but also negates his own luck, much to his chagrin. Tōma meets a young girl named Index - a nun from Necessarius, a secret magic branch of the Church of England, whose mind has been implanted with the Index Librorum Prohibitorum - 103,000 forbidden magical books that the Church has removed from circulation. His encounter with her leads him to meet others from the secret worlds of science and magic. Tōma's unusual power places him at the center of conflicts between the Magicians and Espers in Academy City who try to unravel the secrets behind Academy City, Index, and Tōma's own special power.