"Matsuinu" is set in a dystopian future where humanity is on the brink of extinction due to a mysterious plague that transforms people into monstrous creatures known as "Hollows." The story centers on a young man named Ren, who survives in the ruins of a once-thriving city. Ren is a "Matsuinu," a term given to individuals who possess a unique resistance to the plague and are tasked with hunting down Hollows to protect the remaining human settlements.

Ren's journey begins when he encounters a young girl named Aya, who claims to have knowledge of a cure for the plague. Aya is pursued by a powerful organization known as the "Eclipse Syndicate," which seeks to exploit her for their own purposes. Reluctantly, Ren agrees to protect Aya and escort her to a hidden laboratory where the cure is said to be developed. Along the way, they are joined by other Matsuinu, each with their own motivations and tragic pasts tied to the plague.

As the group travels through the desolate landscape, they face numerous challenges, including relentless Hollow attacks, internal conflicts, and the ever-present threat of the Eclipse Syndicate. The narrative delves into themes of survival, sacrifice, and the moral complexities of a world where humanity's survival often comes at a cost. Ren's character evolves from a lone survivor driven by self-preservation to a leader who must make difficult decisions for the greater good.

The story also explores the origins of the plague and the true nature of the Matsuinu, revealing that their resistance comes with a heavy price. Flashbacks and revelations about the characters' pasts add depth to the narrative, highlighting the emotional toll of living in a world ravaged by despair. The climax of the series involves a confrontation with the Eclipse Syndicate, where the fate of the cure and the future of humanity hang in the balance.

The main characters include Ren, the stoic and resourceful protagonist; Aya, the enigmatic girl who holds the key to the cure; and a diverse cast of Matsuinu, each with unique abilities and personal struggles. The interplay between these characters drives the story forward, creating a compelling mix of action, drama, and introspection. The series concludes with an open-ended resolution, leaving room for interpretation about the ultimate fate of the characters and the world they inhabit.