"A Certain Magical Index III" continues the story of Toma Kamijo, a high school student residing in Academy City, a technologically advanced metropolis where students develop supernatural abilities known as "esper powers." Toma possesses the unique ability to negate any supernatural power with his right hand, known as the "Imagine Breaker," though he is classified as a Level 0, the lowest rank of esper. His life becomes increasingly entangled with the conflicts between science and magic, as Academy City's scientific advancements clash with the secretive world of magic users.

The third season adapts the "Battle Royale" and "World War III" arcs from the light novel series, escalating the stakes significantly. The narrative begins with Toma encountering a mysterious girl named Itsuwa, who warns him of an impending conflict involving the Amakusa-Style Remix of Church, a group of Christian magicians. This leads to a confrontation with the Roman Catholic Church's forces, who seek to retrieve a powerful artifact known as the "C-Document," which could destabilize the balance between science and magic. Toma, alongside his allies Index, a nun with a vast repository of magical knowledge, and Misaka Mikoto, a powerful Level 5 esper, becomes embroiled in a series of battles to prevent the artifact from falling into the wrong hands.

As the story progresses, the focus shifts to a global conflict instigated by Fiamma of the Right, a high-ranking member of the Roman Catholic Church. Fiamma aims to use the "Holy Right," a divine power, to reshape the world according to his vision. This leads to the outbreak of World War III, with Academy City and various magical factions drawn into the chaos. Toma, driven by his sense of justice and determination to protect his friends, travels to Russia to confront Fiamma and prevent the destruction of the world. Along the way, he encounters new allies and enemies, including Accelerator, a former antagonist turned anti-hero, and Lessar, a member of the British magical organization New Light.

The season explores themes of power, morality, and the consequences of human ambition, as Toma navigates the complex interplay between science and magic. The narrative delves into the motivations of key characters, such as Fiamma's desire for absolute control and Accelerator's struggle for redemption. The story culminates in a climactic battle between Toma and Fiamma, with the fate of the world hanging in the balance. Through his unwavering resolve and the support of his allies, Toma ultimately confronts the forces threatening global stability, reinforcing his role as a pivotal figure in the ongoing conflict between science and magic.