"Chrono Crusade" is set in the 1920s United States, blending historical elements with supernatural and religious themes. The narrative centers on Rosette Christopher, a nun and exorcist working for the Magdalene Order, a religious organization dedicated to combating demonic threats. Rosette is accompanied by her demon partner, Chrono, who is bound to her through a contract. Chrono, once a powerful demon, has his abilities limited by the contract, which also ties his lifespan to Rosette's. The two share a deep bond, rooted in a tragic past that unfolds as the story progresses.

The plot begins with Rosette and Chrono undertaking missions to exorcise demons and protect humanity. Their primary objective, however, is to find Rosette's younger brother, Joshua, who was abducted by the demon Aion. Aion, a former friend of Chrono, seeks to overthrow the existing order and create a world where demons and humans are equal, though his methods are ruthless and destructive. As Rosette and Chrono pursue Aion, they uncover layers of conspiracy involving the Magdalene Order, the origins of demons, and the true nature of their own connection.

Throughout the series, the relationship between Rosette and Chrono is explored in depth. Rosette's determination to save Joshua drives much of the narrative, while Chrono's internal conflict between his demonic nature and his loyalty to Rosette adds complexity to his character. The story also delves into themes of sacrifice, redemption, and the consequences of wielding power, as both protagonists face moral dilemmas and personal losses.

Supporting characters include Sister Kate, a fellow nun and Rosette's close friend, and Azmaria, a young girl with a mysterious connection to the divine. These characters contribute to the emotional and thematic depth of the story, providing additional perspectives on the central conflicts. The narrative builds toward a climactic confrontation with Aion, culminating in a resolution that ties together the fates of Rosette, Chrono, and Joshua.

"Chrono Crusade" combines action, drama, and supernatural elements, creating a compelling story that balances intense battles with poignant character moments. The series is notable for its exploration of faith, humanity, and the bonds that transcend even the boundaries between species.