Following Armageddon, an apocalyptic war, mankind faces yet another menace: vampires. The continuous confrontations between the races have split the world into separate factions. The race of vampires, Methuselah, are affiliated with the New Human Empire; whereas the humans, deemed Terrans by the vampires, make up the Vatican Papal State. Furthermore, extremist groups like the Rosenkreuz Order strive to rekindle a war, despite the factions' attempts to avoid direct conflict.

To combat terrorist organizations, the Vatican has implemented the AX unit. Led by Cardinal Caterina Sforza, the AX agents investigate vampire-related disturbances with hopes that the Terrans and the Methuselah will one day achieve peaceful coexistence. Amongst the AX unit is priest Abel Nightroad—a seemingly disoriented but gentle-hearted fellow who is a fierce vampire slayer on the battlefield. Joining the unit as his partner is agent Sister Esther Blanchett, a brave and gentle young nun troubled with a tragic past.

As the two grow closer, they begin to uncover signs of malicious schemes and dark forces working in the shadows. But the path they walk is riddled with misfortune that might just force them to confront the memories that plague their hearts.

Trinity Blood premiered in Japan on the satellite network WOWOW on April 28, 2005 and ran until October 6, 2005. The satellite channel Animax also aired the series across its networks. The Funimation English dubbing of the series premiered on Canadian television on the Razer network on July 6, 2006; and in the United States as part of Cartoon Network's Adult Swim block on September 9, 2006.

The series enjoyed strong television ratings when it originally aired in Japan. Its North American debut was also considered successful; it is credited for being one of four Funimation properties that helped the company achieve a 47.8% sales gain in 2006.

Funimation gave Trinity Blood a 90-minute US theatrical release to promote the series. The film, titled Trinity Blood: Genesis, is a compilation of the first four episodes of the series and released on May 5, 2006 in conjunction with Anime Central in Chicago, IL.