Ever since a powerful king established a truce eons ago between the beings of his mythical world and that of the humans, the two worlds have coexisted peacefully, even if the latter doesn't believe in the former save for nightmares and children's stories. That's about to change when the king's son, Prince Nuada (LUKE GOSS), has had enough of the humans laying waste to the natural world and is determined to get rid of them once and for all.
Thus, and despite the objections of his twin sister Princess Nuala (ANNA WALTON) and their father, Nuada sets out to resurrect an ancient but indestructible golden army of mechanical soldiers to do the job. The only problem is that he needs to reassemble three pieces of a magical crown that will give him control of the army. By Forcibly collecting part of that from a Manhattan antiquities auction, he draws the attention of the Bureau of Paranormal Research and Defense (BPRD), a covert branch of the FBI comprised of both humans and various mutants.
Things aren't peachy keen there, however, as Head of Special Operations agent Tom Manning (JEFFREY TAMBOR) is concerned that less than covert public appearances by Hellboy (RON PERLMAN), a mutant and devilish superhero spawned by the occult but raised with humans to battle evil, will blow their cover.
That's particularly true since Hellboy (with his filed down devilish horns, tail and gargantuan concrete-like fist) doesn't seem to care, especially when he's trying to figure out why his coworker and fire-starter girlfriend, Liz Sherman (SELMA BLAIR), seems to want to break up with him, unaware of what psychic fish-man Abe Sapien (DOUG JONES) knows is in store for them.
After their cover is blown, protoplasmic entity Johann Krauss (voice of SETH MacFARLANE) is brought in to run the division, a development that doesn't sit well with Hellboy for a number of reasons, the least of which is that he doesn't trust Germans (due to his own origins associated with WWII era Nazis).
As Prince Nuada continues on his quest to reassemble the magical crown and thus resurrect the Golden Army, and Princess Nuala goes on the lam to try to prevent that from happening, Hellboy and his comrades must battle him and the various otherworldly beasts and creatures he deploys.