The plot focuses on Akane Tsunemori, a new Inspector of Unit One—a police unit from the Public Safety Bureau's Criminal Investigation Division. Tsunemori hunts criminals alongside a special team of so-called latent criminals called Enforcers. Inspectors and Enforcers use large handguns called "Dominators"—special weapons designed to fire only at those with a higher-than-acceptable Crime Coefficient. Akane is ashamed of shooting the Enforcer Shinya Kogami during her first mission to protect a latent criminal. Kogami thanks her for stopping him from becoming a murderer, which persuades Akane to stay. She is accompanied by veteran Inspector Nobuchika Ginoza, a strict man who looks down on Enforcers, Tomomi Masaoka, a middle-aged man who used to be a detective, Shusei Kagari, a carefree young man who has been a latent criminal ever since he was a child, and Yayoi Kunizuka, a former musician turned into a latent criminal after interacting with a terrorist. During Akane's first investigations, the group learns about the existence of Shogo Makishima, a mastermind who is responsible for multiple crimes. Being Criminally Asymptomatic (免罪体質 Menzai Taishitsu?), Makishima's criminal psychology yields a low Crime Coefficient, making him safe from the Sibyl System and the Dominator.
The Enforcers and Inspectors start hunting Makishima, who aims to destroy the society created by the Sibyl System. To do this he causes riots in the city to draw the police away from the Health and Welfare Ministry's Nona Tower facility, where Sibyl is located. Akane and Kogami stop Makishima's forces while Enforcer Shūsei Kagari follows one of Makishima's allies to the tower where Bureau Chief Joshu Kasei kills Makishima's ally and Kagari to keep the true form of Sibyl a secret. Kasei tells Makishima that Sibyl is a hivemind of similarly asymptomatic individuals and wishes him to join the system but Makishima escapes. Realizing the truth behind Makishima's escape, Kogami leaves the group to kill him. Akane is later directly contacted by the Sibyl system, which orders her to capture Makishima alive. She agrees to do this on the condition that they withdraw the execution order for Kogami. Learning that Makishima plans to commit bioterrorism to weaken Japan's economy and bring the system down, the Criminal Investigation Division searches for both Makishima and Kogami. There, Makishima tries killing Ginoza but Masaoka sacrifices his life to save him. Despite Akane's efforts, Kogami kills Makishima and the former's erstwhile comrades never see him again.
In season two, Akane, now the leader of a restored Unit One including rookie inspector Mika Shimotsuki, Ginoza, who is demoted to an enforcer, Yayoi and two new enforcers, Sakuya Togane and Sho Hinakawa, face a new threat in the form of Kirito Kamui, another criminal mastermind who, just like Shogo, intends to bring down the Sybil System by exploiting its flaws instead of just wreaking havoc. Skilled in avoiding all forms of detection and capable of helping his supporters to keep their Crime Coefficients low, only a very few believe that he actually exists, including Akane.