The background is in the distant future, a post-apocalyptic world after the destruction brought about by Armageddon. The war between humans (Terran) and vampires (Methuselah) continues, as a struggle between two factions: the Vatican and the New Human Empire.

Yet, amidst the bloodshed and violence, many desire a peaceful co-existence between the two species. However, standing between them and this goal is the Rosenkreuz Orden, a group of vampire extremists who manipulate the two sides and pit them against each other. To combat them, the Vatican special operations group "AX," led by Cardinal Caterina, must use everything they have—even a vampire who preys on the blood of other vampires.

Trinity Blood: Rage Against the Moons was left unfinished due to the death of author Sunao Yoshida. The first four volumes were published in English by Tokyopop from April 10, 2007 to April 27, 2010.