Isuca follows Shinichirou Asano, a broke high school student who has been left on his own by his parents and spends his days trying to keep up with classes, job hunting, and the constant strain of living with almost nothing. One night, his bleak routine is shattered when a centipede monster attacks him and he is saved by Sakuya Shimazu, a fellow student and gifted archer from a family of exorcists who fight rogue creatures.
When Shinichirou accidentally releases a nekomata, a two-tailed demon cat, he is pulled even deeper into Sakuya's supernatural world and the dangerous incidents that surround her. The two begin working together, with Shinichirou taking on the unusual role of housekeeper and protector while Sakuya continues to confront the threats her lineage is sworn to eliminate. As one strange encounter follows another, their uneasy partnership slowly hardens into trust, and Shinichirou starts to find a sense of purpose in the chaos that follows them.
