Kaiju No. 8 is set in a world where Japan experiences the highest rate of Kaiju attacks. Kafka Hibino is a 32-year-old man who works for a Kaiju disposal company that deals with the cleanup of Kaiju remains. As a child, Kafka made a promise with his childhood friend, Mina Ashiro, that they would "eliminate all the Kaijus" together.

Now, Mina has become the captain of the Third Division of the Defense Force, while Kafka has given up on his dream of joining the Defense Force and leads an ordinary life. During a mission, Kafka is infected by a mysterious creature, transforming his body into a Kaiju. He then becomes known as "Kaiju No. 8", who retains his human consciousness but possesses the strength and abilities of a Kaiju.

After using his newfound power to save civilians, Kafka is inspired by the vision of fighting alongside Mina and decides to join the Defense Force to fulfill his childhood promise.