In the final days of World War II, the Nazis attempt to use black magic to aid their dying cause. The Allies raid the camp where the ceremony is taking place, but not before they summon a baby demon who is rescued by Allied forces and dubbed "Hellboy". Sixty years later, Hellboy serves the cause of good rather than evil as an agent in the Bureau of Paranormal Research & Defense, along with Abe Sapien - a merman with psychic powers, and Liz Sherman - a woman with pyrokinesis, protecting America against dark forces.

A CIA operation to purchase classified Russian documents is blown by a rival agent, who then shows up in the sleepy seaside village where Bourne and Marie have been living. The pair run for their lives and Bourne, who promised retaliation should anyone from his former life attempt contact, is forced to once again take up his life as a trained assassin to survive.

After losing their baby, a married couple adopt 9-year old Esther, who may not be as innocent as she seems.

Blade forms an uneasy alliance with the vampire council in order to combat the Reapers, who are feeding on vampires.