Dean becomes more aggressive as a demon, and Crowley tells him it's because the Mark of Cain needs to be fed. Meanwhile, Sam is captured by an angry man who blames Dean for his father's death and wants revenge; and Hannah asks Metatron for help when Castiel's grace continues to fade.
Dean learns that Bobby or his next of kin have been named as a beneficiary in an heiress' will, so he convinces Sam to take a road trip with him to claim their fortune. But when they arrive, things aren't quite as they had hoped or imagined.
Rowena returns and tries to recruit and train followers in the art of witchcraft, but Sam and Dean devise a plan to stop her. Meanwhile, Hannah runs into a blast from her vessel's past, which complicates things for her and Castiel.
Jody Mills reluctantly attends a mandatory sheriff's retreat and is partnered with an overeager sheriff who wants to bond. Even worse, a body with just strings of meat and skin hanging off the bones is discovered. Jody calls Sam and Dean for help.
Castiel finds Jimmy's daughter Claire in a group home and she convinces him to break her out. After she runs away from him, Castiel calls Sam and Dean to help find her before she gets into trouble. Meanwhile, Crowley faces his biggest challenge.
Sam and Dean double their efforts to find a cure for the Mark of Cain, after the massacre at the ranch. Meanwhile, Rowena plots against Crowley; and Castiel tries to mend his relationship with Claire, who is bent on revenge against Dean for killing her friend.
Charlie returns from Oz and is seen on video beating up a district attorney. Dean suspects she is hunting on her own and that the D.A. must be a demon. When Sam and Dean find her, they are shocked to learn the real reason for her return.
Sam and Dean investigate when people suddenly disappear into thin air with only their clothes left behind. Their probe reveals that Hansel, from Hansel and Gretel lore, is kidnapping people and turning them into their younger selves to placate an evil witch. Unfortunately, Dean finds the information out the hard way when he becomes Hansel's next victim and reverts to being his 14-year-old self.
Sam and Dean investigate a series of suicides committed by people who all killed themselves with self-administered disembowelment. The probe reveals the victims were all members of a Catholic church and had recently given confession. Meanwhile, Crowley captures Olivette, the leader of the Grand Coven; and Rowena pleads her case to once again be allowed to practice magic freely.
Charlie calls Sam and Dean and tells them she found the Book of the Dead that could help remove the Mark of Cain. Unfortunately, a man who claims the book belongs to his family shoots her. Meanwhile, Castiel and Metatron take a road trip to find Castiel's grace, but the journey doesn't go as planned.
Sam and Dean investigate a bizarre murder and realize the killer has the same tattoo as those from the Styne family. Meanwhile, Castiel acts a referee when Charlie and Rowena are forced to work together on the Book of the Damned; and Crowley discovers his mother is missing, so he turns to an old enemy for help.
Season 10 ends with Dean making a shocking decision regarding the Mark of Cain that may change not only his life but Sam's too. Meanwhile, Crowley and Rowena face off, and Castiel gets caught in the middle.