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In 517 A.D., the evil Blood Queen Vivienne Nimue unleashes a plague on England until King Arthur thwarts her with the aid of Ganeida, a member of her coven. Arthur uses Excalibur to dismember Nimue and hides her remains across England. In present-day Tijuana, Mexico, paranormal investigator Hellboy accidentally kills missing agent Esteban Ruiz, who has been transformed into a vampire, during a wrestling match. After hearing Ruiz's dying words, prophesying that the end is coming, Hellboy is brought back to the BPRD in Colorado. He is assigned by B.P.R.D. leader Trevor Bruttenholm, his adoptive human father, to assist the Osiris Club in hunting three giants in Great Britain. The club's seer, Lady Hatton, reveals Bruttenholm was meant to kill Hellboy when he came into the human world as a result of the Nazis' Project Ragna Rok but instead raised him. Meanwhile, a pig-like fairy known as Gruagach is advised by the witch Baba Yaga to retrieve Nimue's limbs so that she may grant his wish for revenge against Hellboy.

During the hunt, Hellboy is betrayed and nearly killed by the hunters before they are ambushed by the giants. Hellboy fights and kills the giants until he collapses from exhaustion, only to be rescued by a young woman. He awakens in her flat, recognizing her as Alice Monaghan, a medium he once rescued from fairies as a baby. Sending an SO19 team to retrieve Hellboy, Bruttenholm introduces Hellboy to M11 agent Ben Daimio and relays that Nimue's remains have been taken, and the last piece is stored at the Osiris Club. Finding the club slain, Alice channels Hatton's spirit, who reveals that Nimue seeks Hellboy to cause the apocalypse. Nimue's arm is taken by Gruagach, and Nimue distracts Hellboy by appealing to his frustrations, allowing Gruagach to escape. Hellboy reveals that Gruagach is a changeling who took baby Alice's place before Hellboy branded him with iron and forced him to return Alice, which led to Gruagach hating Hellboy for taking his chance to be human.

Daimio takes them to M11 headquarters before secretly acquiring a special bullet to kill Hellboy. After an argument with Bruttenholm about his adoption, Hellboy angrily storms off until he is magically transported to Baba Yaga's house. Having shot out Baba Yaga's eye, Hellboy is talked into giving up one of his eyes for Nimue's location. Hellboy reneges on the deal and is cursed to lose a loved one. On the way to Nimue's location at Pendleton, Daimio reveals to Alice that he was the sole survivor of a demonic jaguar attack.

Nimue fully restores herself and kills her coven, but spares Ganeida. Hellboy attempts to stop her, but is overwhelmed. Nimue poisons Alice and flees, as Ganeida directs Hellboy to the resting place of Merlin to save Alice. After Merlin cures Alice and puts her and Daimio to sleep, he reveals that Hellboy is Anung un Rama, heir of Arthur through his mother, who was spirited to Hell by his father. When offered Excalibur, Hellboy refuses after seeing a vision of himself causing the apocalypse, while Merlin, having exhausted his magic, disintegrates.

Meanwhile, Nimue attacks M11 and abducts Bruttenholm as the group follows her to St Paul's Cathedral. Hellboy battles an empowered Gruagach aided by Daimio in his jaguar form. However, Nimue betrays and kills Gruagach and propels Hellboy into Arthur's hidden tomb that holds Excalibur. Nimue kills Bruttenholm and an enraged Hellboy pulls out the sword, allowing demons to emerge from Hell. Alice channels Bruttenholm's spirit to appeal to Hellboy's humanity, allowing him to decapitate Nimue and toss her head into Hell after the demons are sent back. Hellboy and Bruttenholm exchange farewells and Daimio discards the special bullet.

Six months later, Hellboy, Daimio and Alice raid the Oannes Society where they find the water tank of Abe Sapien. In a mid-credits scene, Hellboy is consoled at Bruttenholm's grave by the ghost of his hero Lobster Johnson. In a post-credits scene, Baba Yaga enlists an unseen force to seek out Hellboy with the promise of allowing him to finally die.

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