The movie opens with the voice of Professor Broom (John Hurt) asking a question that will shadow the rest of the film: "What is it that makes a man a man'? Is it his origins- the way things start"??? The voiceover goes on to give some backstory: it is 1944, nearing the end of World War 2, and Hitler is resorting to the occult in a desperate attempt to turn the tide of war in his favor.
The scene opens on an island off the coast of Scotland, where young Professor Broom requests that the military personnel be given rosary beads before continuing on the assignment. But the sergeant in charge just laughs at Broom, thinking him a paranoid moron.
American troops arrive at a set of ruins and find a group of Nazi scientists led by Rasputin and his mistress, IIsa. They are protected by a mysterious figure in a gas mask named Kroenen, reportedly Hitler's top assassin.
Rasputin attaches himself to a mysterious device designed to open a portal to another dimension and awaken forces known as "The Seven Gods of Chaos." Just as the portal opens, the American troops launch grenades into the site, killing some scientists.
Kroenen attacks the Americans, killing several and wounding Professor Broom in the leg. Broom crawls over to a fallen soldier and picks up a grenade, hurling it just beneath the portal. Kroenen breaks off his attack and tries to remove the grenade, but cannot get to it in time. The grenade explodes, destroying the portal and Kroenan's right hand. Kroenen is then impaled by a fragment from the portal and is presumed dead. Rasputin is unexpectedly sucked into the portal, closing it.
Professor Broom has his leg bandaged while instructing the remaining soldiers to search the island- fearful that something may have come through the portal before they could close it. Broom and another soldier suddenly encounter a strange red ape-like creature with a massive stone hand. The soldiers are fearful, but Broom manages to attract the creature with a Baby Ruth candy bar. They realize that this creature, whatever it may be, is just an infant and is essentially harmless to them. The soldiers give the creature a name based on its demonic appearance: "Hellboy."
The movie's credits then show Hellboy's position in modern-day society, effectively as an "urban legend" like Bigfoot or other such creatures.
Fast-forward sixty years and a much older Professor Broom is being examined by doctors. The findings are not good; he has cancer and not much can be done about it. On his way home, Broom sees his friend Tom Manning (Jeffery Tambor) on TV, answering questions about a recent photograph supposedly taken of Hellboy. Manning denies Hellboy's existence.
Meanwhile, a lone figure on a motor scooter arrives at a waste management plant. He activates the speaker-phone and identifies himself as John Meyers (Rupert Evans), a recent graduate of FBI training supposedly reporting for his first assignment. He is taken downstairs by a secret elevator and ends up in a gigantic library with a water tank in the middle of the room. A strange voice asks Meyers to turn the pages on some books, and a strange fish-like humanoid reveals itself inside the tank. Professor Broom arrives and introduces the fish-man as Abe Sapien (voiced by David Hyde Pierce). Meyers is about to introduce himself, but Abe interrupts by reciting a number of facts about Meyers supposedly out of nowhere. Broom explains that Abe has a unique brain, allowing him certain telepathic abilities. Broom feeds Abe a few rotten eggs-a strange delicacy that Abe has acquired a taste for. Professor Broom explains that this is the Bureau for Paranormal Research and Defense (BPRD), and Meyers is their newest ally.
The scene shifts to snowy mountains far away. IIsa and Kroenen are hiking to a sacred location. They kill their guide and use his blood to ressurect Rasputin.
Meyers is given a brief history of the BPRD and its activities, and is then introduced to his superior, Agent Clay. Broom gives Meyers 2 Baby Ruth bars and wishes him well. Clay brings Meyers into a huge vault like room and introduces the BPRD's pride and joy: Hellboy, now an adult (played by Ron Pearlman). Hellboy is less than eager about Meyer's arrival, seeing him as just another of the endless security measures he must live under. Midway through their introduction, an alarm sounds and Hellboy joyfully sets out to "go to work."
A newscaster remarks that an alarm was triggered at a local museum, and that there has been no response from the guards inside. Clay brings Hellboy and Abe Sapien (wearing a type of scuba-suit to keep his gills hydrated), reporting that there is a large monster of some type inside the museum. Professor Broom (whom Hellboy calls "Father"), explains that a statue was destroyed and something trapped inside was freed. Hellboy loads up his trademark weapon, the Samaritan, and goes inside to investigate while Abe tries to research what the creature could be.
Abe comes up with the name "Sammael" for this creature and tells Hellboy about it just as Hellboy encounters the creature. Hellboy shoots the monster a few times and walks away, just as Abe informs him that Sammael is also known as "the Hound of Resurrection." Hellboy turns around and is attacked, eventually thrown out a window. Hellboy encounters Rasputin, finding his voice familiar. Rasputin gives an ominous warning about Hellboy's future before Sammael attacks again. Meyers shows up and shoots Sammael, much to Hellboy's disdain (he doesn't like being helped).
Hellboy attempts to reload his weapon when Meyers notices a strange seed-like creature on Hellboy's arm. Hellboy rips it off and gives it to Meyers, instructing him to save it for study. Hellboy shoots Sammael with a tracking bullet that leaks green fluid, making an easily traceable trail. Hellboy follows Sammael through a crowd and across several lanes of traffic. Meyers tries to keep up but is injured by a passing car and faces certain death before Hellboy returns to block the oncoming car and allowing Meyers to get across.
Hellboy follows Sammael into a subway system, briefly losing contact when a passing train goes over his head. Fed up with the fight, Hellboy grabs the train track and electrocutes Sammael. Hellboy is unharmed by the attack because he has a resistance to fire. Wanting some freedom, Hellboy turns off his radio and goes to see his old friend Liz Sherman (Selma Blair), who used to stay at BPRD but has committed herself to a mental hospital. Meyers and some other agents finally arrive to take Hellboy back. Meyers looks up Liz Sherman's file and finds that she is a pyrokinetic (having the ability to start fire by thought) and that in her childhood she accidentally caused a huge blaze that cost dozens of lives.
Tom Manning and Professor Broom are discussing Hellboy's latest activities. Manning is NOT happy with Hellboy or any of the people at BPRD, whom he calls "freaks." Abe Sapien uses his telepathy to show Professor Broom what happened at the museum: Kroenen killed the guards while Rasputin freed Sammael, enchanting the beast with a type of magic that will make 2 new creatures arise for every one that dies. Abe also learns through the telepathic exchange that the Professor is very sick, and the professor begs Abe to keep this secret from Hellboy.
Hellboy is being examined by Abe and Broom back at base. They find a cluster of eggs in Hellboy's arm where the spore-like object was attached. Broom decides that Hellboy will go back to the subway the next day and look for any more eggs.
That night, Rasputin visits Liz (in secret) at the mental hospital. He uses his powers to unlock her worst memory (the day of the explosion) and activating her fire-starting abilities, destroying the hospital.
Hellboy and Broom discuss this the next morning while Hellboy files his horns (something he does regularly to appear more "Normal"). Meyers offers to speak with Liz and hopefully recruit her into the BPRD once more.
Hellboy, Clay, Abe and two other agents return to the sewers to find the Eggs. Abe jumps into a cistern to capture a cluster of eggs, but is attacked and badly injured by another Sammael. The two agents are attacked and killed by yet another Sammeal, which Hellboy chases after. Clay is left behind and winds up getting stabbed by Kroenen, who then apparently commits suicide.
Hellboy chases Sammael into a subway station, finally killing him again by smashing the monster into an oncoming train. Hellboy returns, shocked to find his friends wounded.
Back at BPRD, Manning reveals that Abe will recover but Clay is too badly wounded and most likely will not survive the night. Manning and Hellboy clash, both angry about what has happened. Meanwhile, Liz has decided to come back to BPRD.
Hellboy is in his room, struggling to write a letter for Liz that describes his feelings for her when Liz comes in and reveals that she is going on a date with Meyers. Hellboy is angry, but puts it aside and decides to follow them.
Broom is doing an autopsy of sorts on Kroenen, where he learns that Kroenen is over 100 years old and his body is badly mutilated (due to a form of masochism). When the professor leaves, Kroenen uses a type of clockwork mechanism to restart his heart and allows Rasputin into the BPRD. Rasputin confronts the professor, taunting him for not knowing Hellboy's true purpose or name. Broom responds that-as far as he is concerned- Hellboy's proper title is "Son." Rasputin grants Broom a glimpse into the future, where Hellboy is responsible for Armageddon. Kroenen then executes Professor Broom.
Meyers and Liz are still on their date (with Hellboy watching) when they are told what has happened. Hellboy is devestated by the loss, refusing to eat or speak for days. Manning takes over the BPRD (a job he does not relish) and announces that he will lead a team to Russia to find the source of Sammael's eggs.
In Russia, Hellboy re-animates a corpse with magic and gets directions to Rasputin's Mausoleum. The group is divided inside, with Liz & Meyers in one direction and Hellboy & Manning in another. Hellboy and Manning find Kroenen's hiding place, and Hellboy saves Manning's life by attacking Kroenen with his stone fist. Kroenen attempts to lure Hellboy into a spiked pit, but Manning throws a gear at Kroenen, blocking his attack. Hellboy knocks Kroenen into the pit and kills him with a gigantic gear. Hellboy and Manning thank each other for their endeavors, having formed a type of mutual respect.
Liz and Meyers find the egg chamber. Hellboy joins them, but he is overwhelmed by Sammael duplicates. Liz begs Meyers to attack her, hoping that it will trigger her fire-powers. It works, and Sammael (eggs and doubles) are destroyed for good. But Rasputin and IIsa take the opportunity to capture Hellboy and his friends.
Rasputin wants Hellboy to use his "Right Hand of Doom" to finally free the Seven Gods of Chaos. Hellboy refuses, but learns that Liz is critically injured and may not survive. He agrees to Rasputin's terms and speaks his true name- "Anung-Un-Rama." Hellboy's horns suddenly grow to full length and he begins to breathe smoke, having embraced his "Demon" heritage.
Meyers is able to free himself before Hellboy opens the final seal of the Gods. Meyers begs Hellboy to remember who he is, and throws the prayer-beads that once belonged to Professor Broom. Hellboy remembers that he does not have to be evil; he has a choice- and his father died so he could make that choice. Hellboy rips off his horns and stabs Rasputin with them, stating that he doesnt' need Rasputin to tell him who he is. Rasputin's death unleashes a monster (the last envoy of the Seven Gods, called Behemoth) that quickly grows in size.
Hellboy gets Meyers and Liz out of the room, and Meyers gives him a weapon- a cluster of grenades intended for use on Sammael's eggs. Hellboy has a long fight with the Behemoth before finally getting the huge monster to swallow the grenades, destroying it.
Hellboy returns only for Meyers to say that Liz has no pulse. Hellboy kneels down and speaks some words of apparent prayer, and Liz opens her eyes. She asks what he said. Hellboy responds that he was talking to those "on the other side," imploring them to give up Liz because he would gladly cross over himself to try and save her. Moved by his sentiments (and by the events of the last few days), the two kiss passionately. Liz's fire engulfs them both in moments, but Hellboy, being fireproof, is unharmed.
Meyers stands on and concludes Professor Broom's earlier thoughts: "What is it that makes a man a man?' It's the choices he makes. Not how he starts things- but how he decides to end them."