One day, a strange fog descended upon the Japanese island of Kibitsujima. When it cleared, the landscape had been irrevocably altered, and colossal, nightmarish creatures now roamed the land. These beings, known as Super Beasts, began appearing one by one, each leaving a trail of death and destruction in its wake. In response to this existential threat, a specialized organization known as the Ward Office is formed to combat and contain the creatures. The protagonist is Kazuki Kisaragi, a psychologist who is assigned to this dangerous duty. Rather than flee the disaster zone, Kisaragi sails directly into the chaos, appointed as the Section Chief of Security Section 4.

Kisaragi quickly discovers that his new role is far more complex than simply fighting monsters. He learns that the Ward Office utilizes genetically altered girls, dubbed witches, who have been infused with Super Beast DNA to give humanity a fighting chance against the creatures. His primary assignment is not tactical leadership but to act as a therapist for these witches, monitoring their mental state to prevent the beast cells from taking over their bodies and causing them to rampage. He is joined by a cast of compelling characters, including the no-nonsense Security Division Supervisor Sumire Hasegawa, the cold-hearted Chief Tomohiko Munehiro, and the razor-sharp witch agent Miko Mikoshiba, a seemingly emotionless girl who has accepted her expendability.

The narrative follows Kisaragi as he struggles to connect with Mikoshiba and understand her trauma, balancing his psychological duties with the constant threat of Super Beast attacks. The series builds its world by exploring the origins of the witches. The organization known as the Beast Workers Union explains to Kisaragi the nature of the beasts and the potential they hold for humanity, revealing that the line between human and monster is terrifyingly thin. This leads Kisaragi to make a crucial decision regarding the future of the witches under his command. The conflict escalates dramatically with the appearance of the strongest level Super Beast, Screamer, whose power surpasses anything the Ward Office has faced before, pushing their forces to the brink.

As the story progresses into a full-scale war for the island, the Security Section discovers that not all monsters are purely mindless forces of nature. During a mission to restore a hydroelectric power plant, they encounter the Super Beast called Keukegen, only to realize it was originally a witch who lost control and transformed. This revelation adds a tragic layer to their mission. The final volume finds the world teetering on collapse, with the team fractured and trust in short supply after a betrayal by the rogue witch Ayame. As the most powerful Super Beast yet emerges with terrifying intelligence and a devastating agenda, the surviving members of the task force must unite one final time, blurring the lines between science and sorcery in an apocalyptic battle to decide the fate of humanity itself.