"A Certain Scientific Railgun" is set in Academy City, a technologically advanced metropolis where students develop supernatural abilities known as "espers." The story centers on Mikoto Misaka, a Level 5 electromaster with the ability to manipulate electricity, making her one of the most powerful espers in the city. Known as "The Railgun" for her signature move of firing a coin at hypersonic speeds, Mikoto navigates the complexities of her abilities while balancing her life as a middle school student.

The narrative explores various arcs, often blending action, mystery, and science fiction. Early arcs focus on Mikoto and her friends—Kuroko Shirai, a teleporter and member of the Judgment disciplinary committee; Kazari Uiharu, a tech-savvy classmate; and Ruiko Saten, a Level 0 esper with no powers but a strong sense of justice. Together, they investigate strange occurrences in Academy City, ranging from urban legends to sinister experiments.

A significant storyline involves the "Level 6 Shift Project," a clandestine experiment aiming to create the first Level 6 esper by cloning Mikoto. The clones, known as the "Sisters," are used in a series of battles against Accelerator, the top-ranked Level 5 esper, who seeks to achieve Level 6 by killing them. Mikoto discovers the project and struggles to stop it, confronting both the ethical implications of her clones' existence and her own feelings of guilt and responsibility.

Later arcs expand on the world of Academy City, introducing new threats such as the enigmatic organization ITEM, composed of powerful espers, and the dark underbelly of the city's scientific experiments. The series also delves into the broader "Toaru" universe, intersecting with events from "A Certain Magical Index," though it maintains a focus on Mikoto and her friends.

Themes of friendship, morality, and the consequences of unchecked scientific ambition are woven throughout the narrative. Mikoto's growth as a character is central, as she grapples with her immense power, her desire to protect others, and the ethical dilemmas posed by the city's experiments. The series balances intense action sequences with moments of camaraderie and introspection, creating a multifaceted exploration of its characters and setting.