Tha anime revolves around the activities of The Order of Magdalene, an organization of the Catholic Church that banishes devils and demons to Hell. The Order has many branches around the country; each one is presided over by the Council of the Catholic Church. The New York Branch of the Order is headed by Kate Valentine and Ewan Remington, who lead the fight against the forces of darkness. The Order has many members; however, in times of great crisis, other less generally accepted individuals may be introduced into the Order to help fight the forces of darkness.
They use various weapons, including various guns and swords. Guns use Sacred, standard bullets containing Holy Water, and Gospel, bullets with alchemized silver. Tetragramaton, a gun with high power against demons with low backlash, is given to Chrono. Besides using guns, there are members of Order with special powers as well, using devices like tomes, violins, or dolls. They also use Angel Capture Fields, specialized barriers that can repel demons, their power, and other astral based substances, and Soul Dive, an experimental system used to dive into souls. The order uses the Barrier Ship \"Metatron\" during great crisis.
Chrono Crusade is set in the height of the Roaring Twenties, where jazz is king, bootleg liquor flows freely, and the mob rules the streets. It is a time of prosperity, luxury and decadence, and the division between rich and poor grows even wider in the wake of the First World War. It is at such times of great change and upheaval that the dark things that lurk below the world of man can come to the surface. In the world of Chrono Crusade, a fictional organization known as the Order of Magdalene (or more specifically, the characters of Sister Rosette Christopher and her soul-bound demon partner, Chrono) exists to fight the demonic threats that appear with increasing regularity across America. Both Rosette and Chrono are revealed during the course of the story to be driven by a shadowy past, centered around a search for Rosette\'s lost brother, Joshua. Joshua is shown to have been taken from her by the sinner, Aion, a devil who shares a dark and bloody history with Chrono, and seeks nothing less than to overthrow Heaven and Earth.
The anime follows the manga through the first half, but it diverges halfway through, creating different courses of events and endings. The characterization of some the characters, including Rosette and Aion, and their roles in the story were changed in the adaptation of the manga. Much of the story is driven by the individual pasts of the main characters and the complex relationships between them.