In a Japan where giant monsters known as kaiju are a near-constant threat, the Japan Anti-Kaiju Defense Force is the nation's elite military organization dedicated to their destruction. The story centers on Kafka Hibino, a 32-year-old man who has repeatedly failed the entrance exam for the Defense Force and now works for Monster Sweeper, Inc., a company responsible for the gruesome task of cleaning up the remains of kaiju after battles. His childhood friend, Mina Ashiro, is now the celebrated captain of the Defense Force's Third Division, a constant reminder of the promise they made as children to stand together against the monsters. After a fateful encounter with a rogue, parasitic kaiju while on the job with a determined new recruit named Reno Ichikawa, Kafka is gravely injured. While recuperating in the hospital, a mysterious small kaiju enters his body through his mouth, granting him the ability to transform into a powerful, humanoid kaiju.

This new form, designated Kaiju No. 8 by the Defense Force, possesses immense strength, speed, and regenerative abilities, with a fortitude level of 9.8, making it one of the most powerful kaiju ever recorded. Despite his newfound power, Kafka retains his human consciousness and, with Reno as his only confidant, resolves to reapply for the Defense Force to fight alongside Mina. He and Reno pass the grueling entrance exams, befriending other recruits including the 16-year-old prodigy Kikoru Shinomiya, the daughter of the Defense Force's Director General, Isao Shinomiya. The trio is assigned to the Third Division, where Kafka must hide his monstrous identity while using his unique knowledge of kaiju anatomy, gained from years of clean-up work, to support his team.

The primary antagonist emerges as a highly intelligent, humanoid kaiju designated Kaiju No. 9, which can speak, assume human form, and command other kaiju. After a brutal attack on the Third Division's headquarters by another powerful monster, Kaiju No. 10, Kafka is forced to transform publicly to save his comrades, leading to his arrest. Director General Isao Shinomiya personally tests Kafka in battle, using a powerful suit made from a defeated kaiju. Kafka, struggling to retain his identity against the parasitic kaiju's influence, ultimately proves he can control his power. Despite the objections of his colleagues, Isao decides to reinstate Kafka in the Third Division, believing humanity will need his strength to survive the escalating kaiju threat.

The first season concludes with the aftermath of Kafka's secret being exposed and the formation of a fragile new status quo as he continues his duty within the Defense Force. The story continues into a second season where Kafka and Kikoru are transferred to the First Division, led by the formidable but slovenly Captain Gen Narumi, considered Japan's strongest anti-kaiju weapon. As new and more powerful numbered kaiju emerge, created by the cunning Kaiju No. 9, Kafka must learn to control his powers while navigating a military hierarchy that views him as both a valuable asset and a potential threat.