"Trinity Blood" is set in a post-apocalyptic world where humanity is divided between humans and vampires, known as Methuselah. The story unfolds in a future where Earth has been devastated by a catastrophic war, leading to a fragile coexistence between the two species. The Vatican, a powerful religious and political entity, plays a central role in maintaining this balance, employing agents from its special operations division, the AX, to combat threats to peace.

The protagonist, Abel Nightroad, is a seemingly meek and clumsy priest who serves as an agent of the AX. Unbeknownst to many, Abel is a Crusnik, a genetically engineered being with vampiric traits but designed to hunt Methuselah. His dual nature as both a protector of humanity and a being with vampiric powers creates internal conflict and drives much of the narrative. Abel is joined by Sister Esther Blanchett, a young nun who becomes his partner and confidante, providing emotional grounding and moral support.

The plot revolves around the escalating tensions between humans and Methuselah, exacerbated by the actions of extremist factions on both sides. The Methuselah Empire, led by the enigmatic Empress Augusta Vradica, seeks to dominate humanity, while human factions within the Vatican and beyond struggle to resist. The series explores themes of power, faith, and the blurred lines between good and evil, as characters navigate a world where alliances are fragile and motivations are often ambiguous.

Key antagonists include Cain Nightroad, Abel's estranged brother and a fellow Crusnik, who harbors a deep-seated hatred for humanity and seeks to destroy it. Their fraught relationship adds a personal dimension to the larger conflict. Other notable characters include Ion Fortuna, a Methuselah noble with a tragic past, and Caterina Sforza, the strong-willed Cardinal of the Vatican who oversees the AX and serves as a mentor to Abel.

The narrative is structured around episodic missions undertaken by the AX, interspersed with overarching storylines that reveal the deeper history of the Crusniks and the origins of the Methuselah. The series balances action-packed sequences with moments of introspection, delving into the moral dilemmas faced by its characters as they grapple with their roles in a divided world. The interplay between personal struggles and larger political machinations drives the story forward, culminating in a climactic confrontation that tests the limits of loyalty, sacrifice, and redemption.