Tōma Kamijō, a Level 0 student living in Academy City, has a unique esper ability that allows him to nullify psychic, magical and divine powers, but it also negates his own good luck. He survives a reluctant duel with said ability against Mikoto Misaka, a powerful Level 5 psychic capable of controlling and generating electricity, ending with Mikoto causing a citywide blackout. The next morning, Tōma wakes up to find a young nun from the Church of England hanging off his balcony. Introducing herself as Index, she reveals that she is being chased by magicians because she carries 103,000 grimoires. The two become friends after an embarrassing incident, involving Index proving the existence of magic and Tōma proving the power of his right hand, and they part ways. However, when he returns home from remedial class, Tōma finds Index laying on the ground bleeding and, behind him, a man who calls himself a magician.

The magician introduces himself as Stiyl Magnus and explains that his partner Kaori Kanzaki unintentionally hurt Index as her magical garb was supposed to stop the blow. His mission was actually to protect Index, who possesses photographic memory of the 103,000 grimoires implanted in her mind called the Index Librorum Prohibitorum. Angered by Stiyl's ill treatment of Index, Tōma attacks him, to which Stiyl responds by using fire magic and is surprised when Tōma nullifies the spell. To stop Tōma, Stiyl summons a fire creature known as Innocentius. When Tōma finds himself unable to negate the creature, Index activates John's Pen, her self-protection system personality, to reveal that Innocentius' power comes from runes placed around the building. Tōma defeats Stiyl and Innocentius by setting off sprinklers to wash away the runes. However, because of Index's wounds and Tōma's inability to use magic, he brings Index to the only non-esper he knows, that being his teacher Komoe Tsukuyomi.

After Tōma leaves, Komoe successfully helps Index heal her wounds using an ancient magic ritual but asks Tōma the next morning who she is. When he lies that she is his sister, Komoe spots the fib immediately but decides not to press the issue since she believes it is something he must solve on his own. While Komoe goes out to shop, Tōma learns that Necessarius, the organization that Index belongs to, implanted the Index Librorum Prohibitorum into Index's mind so that she would be a living library for the Church, since reading the originals would curse and taint people. Meanwhile, Stiyl and Kaori continue to watch Index and comment on how her happiness will be short-lived. When Tōma and Index get into a fight and separate, Tōma finds himself in an empty street and meets a girl wielding a nodachi, which so happens to be Kaori.

Tōma refuses to hand Index over to Kaori, who reveals that she is also a member of Necessarius and a dear friend to Index. Kaori never intended to hurt Index when attempting to secure her the day before, unaware that Index's magical garb was previous damaged by Tōma. While eighty-five percent of Index's memory contains the entire Index Librorum Prohibitorum, the remaining fifteen percent needs to be annually erased to avoid any strain with any unnecessary memories, and there is only three days left before the limit is reached. Even though Index would not be able to recall him, Tōma asks Kaori why she does not explain everything to Index. Stiyl and Kaori had tried everything to restore Index's memories, but it became unbearable to see her smile with each successive failure. Tōma criticizes them for not taking Index’s feelings into account each time, questioning why Kaori was hiding this from her. After Tōma is severely injured by Kaori, he wakes up three days later in Komoe's apartment in the care of Index. When Stiyl and Kaori arrive, Index tries to protect Tōma by promising to do as they ask.

Tōma learns that Stiyl and Kaori will come at exactly midnight to perform the spell to erase Index's memory. Despite Tōma's attempts to find another way to save Index, midnight arrives and he is helpless as Stiyl and Kaori arrive to prepare the spell. The duo give him time to say goodbye to Index. In this time, Tōma becomes suspicious of Kaori's statement that Index's memory only has room for daily life to take up fifteen percent. Calling up Komoe, he learns that humans can never suffer or die from being overloaded with information and realizes that the Church regularly erased Index's memory to ensure her loyalty to them and tricked Stiyl and Kaori. Determined to save Index, Tōma tries to dispel a magical rune in her throat, only to activate her John's Pen mode. Unable to analyze and devise a means of countering Tōma's ability, John's Pen activates St. George's Sanctuary, a spell it has determined as the most effective way of eliminating Tōma.

After Tōma convinces Stiyl and Kaori that they were tricked by Necessarius about Index's condition and that destroying the magic responsible for Index's pain will allow her to live a normal life, Tōma is able to disable her John's Pen mode with help from Stiyl and Kaori. However, St. George's Sanctuary remains in effect and Tōma is rendered unconscious when a feather from the spell touches his head. At the hospital, Index discovers that Necessarius will leave her alone for now since Stiyl and Kaori are now questioning why the Church lied about her condition and that Tōma's memories have been erased since the spell destroyed his brain cells. At first, Tōma says that he is unable to recognize Index when she goes to see him, but brushes it off as a joke and explains that he canceled the spell with his right hand's ability, now called Imagine Breaker, before she leaves. What Index does not know is that Tōma really was unable to remember anything but did not want to burden Index with his condition, though feeling that his memories still remain in his heart. Two weeks later, Stiyl meets Aleister Crowley, the ruler of Academy City, and to keep the status quo of non-interference between science and magic, Aleister lends Tōma to Stiyl for an assignment to rescue "Deep Blood", someone capable of killing vampires, from a magician in Academy City.