In the 1950s, B.P.R.D. agents Hellboy and Bobbie Jo Song are tasked with transporting via train a toxic supernatural spider to their headquarters. However, when they cross the Appalachian Mountains, the spider suddenly enlarges to monstrous proportions, forcing their train car to overturn and the spider to escape. Hellboy surmises that the spider grew due to something evil haunting the area, admitting that he heard it calling to him. Left stranded, Hellboy and Bobbie Jo wander until they meet Tom Ferrell, a local who's recently returned to atone for past sins. The agents accompany Tom to speak with Cora Fisher, a witch and Tom's ex-girlfriend, only to find the house and Cora's body empty.
As they wait for the demonic familiar to return with Cora's full body, Tom regales to the agents he once met Effie Kolb, a witch that attracted him towards witchcraft and convinced him to make a deal with an entity known as "The Crooked Man." At Effie's suggestion, Tom used a cat carcass to summon the Crooked Man, that whatever bone he held once the entity arrived would become his lucky bone. However, the sight of the Crooked Man terrified Tom enough to have a change of heart and discard the lucky bone, but it would always return and kept him safe from harm. Tom intends to face the Crooked Man once and for all. When the familiar returns Cora's body, she reveals to Tom that the local witches want her soul.
To Tom's shock, Effie arrives on a white horse to collect Cora's soul. After Hellboy threatens Effie, the white horse suddenly transforms into Tom's father as Effie escapes. Tom and his father reconcile briefly before he dies. The following morning, Tom, Cora, and the agents walk to a nearby church, owned by Reverend Watts, to bury Tom's father, but Cora is attacked and killed by a demonic snake. Hellboy kills it, but its bites show him visions of his mother Sara, a witch who made a deal with a demon.
The survivors reach the church, where they are confronted by the Crooked Man and his servants. Tom is tempted to return his lucky bone but Hellboy stops him. As Hellboy battles the demonic horde, the Crooked Man attempts to entice the blind Reverend with youth and sight in exchange for giving up Tom. Watts refuses to give in to temptation and blesses a shovel with Tom's lucky bone that allows Hellboy to weaken the Crooked Man and neutralize his forces.
Hellboy and Tom chase the Crooked Man to an abandoned mansion but are assaulted with traumatic visions. Bobbie Jo, believing the Crooked Man draws power from the town's mines, reaches a tunnel system via an access under the church. She disrupts the Crooked Man's power source with a spell, which frees Hellboy and Tom from the visions and they destroy the Crooked Man.
In the aftermath, Effie ages rapidly, Hellboy and Bobbie Jo are rescued, Tom feels a weight has been lifted from his soul, and a white horse wanders with a warning written on its hide stating, "Beware! I am a Witch!"
