Fifteen years after graduating from the Massachusetts Institute of Technology, the brilliant but introverted Sou Touma now works as a researcher at the same university. His partner, the athletic and compassionate Kana Mizuhara, is a freshman at nearby Harvard University. The two have reunited in the Boston area, where they once again find themselves drawn into a series of complex and difficult cases.

The story follows Kana as she navigates student life at Harvard while simultaneously being pulled into mysteries that range from the university's hallowed halls to the wider, turbulent landscape of modern America. Sou, now a researcher at MIT, applies his exceptional logical and scientific acumen from across the city. Together, they work to solve cases that reflect the anxieties and divisions of contemporary American society, including political polarization, economic disparity, and the far-reaching influence of the tech industry.

The main characters retain their classic dynamic. Sou Touma is a genius with a childlike fascination for simple phenomena and a deep well of knowledge across multiple scientific disciplines. His deductive reasoning provides the key to solving each puzzle. Kana Mizuhara is a former high school kendo and judo champion, whose strong sense of justice, social intuition, and physical courage allow her to gather information and take action where Sou cannot. Her father, a police detective in Japan, is a supporting presence in their lives.

The series is set primarily in Boston, Massachusetts, shifting the narrative focus from the Japanese high school setting of the original series to the prestigious and high-pressure environment of American academia and its surrounding communities. This new backdrop allows the characters to confront cases tied to the unique culture, history, and problems of the United States.

Notable early narrative arcs include the opening story, Beginning of the UNIV., where Kana, while struggling with a lecture on cosmic inflation theory, becomes entangled in a mystery involving a cursed doll found in a Boston mansion, a case that stretches back sixty years to the 1960s hippie counterculture. Another early arc, Roots, follows a ransomware attack on the computer systems of both Harvard and MIT. A later story, Waterside Horse, deals with the suspicious death of a liberal lawyer who was in a legal dispute with the tech industry, with suspicion falling on his ex-girlfriend, a prominent CEO. Another arc, Invisible Hand, involves Kana in a film project about a three-year-old wrongful murder conviction, where crucial surveillance footage has seemingly vanished.