Season 10 begins with Sam’s frantic search for his missing brother, who is gone without a trace. The road to recovering the wayward Dean takes Sam down dark paths, with consequences that will shake the boys to their core. Meanwhile, Castiel has to pick up the pieces in the aftermath of Metatron’s campaign. With his grace failing and rogue angels still on the loose, Cas will face the ticking clock of his own mortality as all-new threats emerge to once again push all of our heroes to their limits.
Dean is a demon and running amuck with Crowley while Sam tries to figure out what happened to his brother. Meanwhile, Castiel is dealing with his diminishing grace.
Crowley notices Dean is becoming more and more aggressive. Dean tells him that’s the side effect of being a demon, but Crowley knows it’s something more - the Mark of Cain needs to be fed. Meanwhile, Sam is captured by Cole, an angry man who blames Dean for his father’s death years ago and wants revenge. Cole tortures Sam, hoping he’ll tell him where Dean is hiding. Hannah sees how weak Castiel is becoming as his grace continues to fade, so she makes a bold choice and asks Metatron for help.
Sam continues his efforts to save Dean from the Mark of Cain. Crowley realizes Dean’s demonic antics are starting to cause problems for him in Hell so he searches out an unlikely ally.
A recent string of werewolf attacks points to a surprising culprit – Kate, the werewolf Sam and Dean let live.
When Sam and Dean investigate the disappearance of a teacher, they are stunned to see the school is putting on a musical based on their lives.
Dean is surprised when he checks Bobby’s cell phone and hears a message that says Bobby or his next of kin have been named as a beneficiary in an heiress’ will. Hoping that means extra money, Dean talks Sam into hitting the road to claim their fortune. However, what they encounter at the house is far from a treasure chest.
Sam and Dean stumble upon a demon who is running from Crowley. Before they have a chance to shut him down, Rowena steps in and takes things into her own hands. Realizing Rowena is trying to recruit and train followers in the art of witchcraft, Sam and Dean come up with a plan to catch her before she can do much damage. 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 named Donna who wants to bond. Just as Jody thinks things can’t get any worse, a body with just strings of meat and skin hanging off the bones is discovered. While the local sheriffs blame an animal attack, Jody knows better and calls Sam and Dean.
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 in trouble. Meanwhile, Crowley faces his biggest challenge yet.
After the massacre at the ranch, Dean, Sam and Castiel double their efforts to find a cure for the Mark of Cain but there is nothing in the lore that can help them. Desperate, Castiel comes up with an idea that Sam deems the "single worst idea I've ever heard." Meanwhile, Rowena continues to plot against Crowley, and Castiel tries to mend his relationship with Claire who is plotting revenge against Dean for killing her friend.
Sam is scanning the internet for suspicious paranormal activity and comes across a video of Charlie beating up a district attorney. Dean suspects she’s back from Oz and hunting on her own, assuming the district attorney must have been a demon. When they do find Charlie, they are shocked when she tells them why she really came back from Oz.
Looking to get Dean out of the bunker, Sam finds a case for him and Dean to investigate – people are disappearing into thin air with only their clothes left behind. Sam and Dean suspect fairies or angels, but the truth turns out to be much more shocking – Hansel, from Hansel and Gretel lore, is kidnapping people and turning them into their younger selves to placate the evil witch. Unfortunately, Dean finds this information out the hard way after he becomes Hansel’s next victim and reverts to his 14 year old self.
A ghost starts killing people through various electronic devices. Sam and Dean discover who was killed and why this ghost is seeking revenge on a group of college students but what they can’t figure out is how he’s doing it. With three dead, the brothers must stop the ghost before he claims his next victim.
Dean, Sam and Castiel deal with Cain’s return. Crowley and Rowena continue to grow closer but when Crowley bails on plans with his mother to help the Winchesters, Rowena lets him have it.
Despite Dean's directive to forget about looking for a cure for the Mark of Cain, Sam continues to do research. Dean suspects Sam is hiding something but decides to focus on a new murder case where they run into Cole. The three team up and learn a Khan worm is infecting men and turning them into murderers. Unfortunately, the worm makes its way into Cole.
Sam and Dean investigate a string of suicides committed by people with little in common other than the identical, grisly method of death – slow, self-administered disembowlment. All of the victims were members of a Catholic church and had recently given confession, leading the brothers to suspect the priest is somehow involved. Meanwhile, when Crowley captures Olivette, the leader of the Grand Coven, Rowena pleads her case to be allowed to practice magic freely again.
Sam and Castiel follow up on a lead about the Mark of Cain. Dean and Rowena meet.
Charlie calls Sam and Dean to tell them she found the Book of the Dead which could help remove the Mark of Cain. The Winchesters race to her after she tells them she’s been shot by a man named Jacob Styne who says the book belongs to his family and he won’t rest until he gets it back. Castiel and Metatron take a road trip to find Castiel’s grace but they hit a couple road bumps along the way.
Sam learns that former Men of Letters, Magnus, once built a magical box and Sam sets out to find it in the hopes it can cure Dean of the Mark of Cain. However, what he’s not prepared for, is the deadly alarm system Magnus set up on the box. When Sam opens the box, he puts both his and Dean’s life in danger.
When Claire Novak gets a lead on her mother, Amelia, who has been missing for years, Castiel asks Sam and Dean to help her. Castiel feels guilty for what he did to the Novak family and wants to make amends by reuniting Claire with her mom. However, when they find out what took Amelia, they realize there is a chance Claire may not get her happy ending.
Dean and Sam investigate a bizarre murder and realize the killer bears the same tattoo as those from the Styne family. Eldon Styne attacks Dean and a brutal fight ensues. Meanwhile, Castiel acts as referee when Charlie and Rowena are forced to work together on the Book of the Damned. Crowley discovers his mother is missing and knows she's up to something so he turns to an old enemy for help.
When it comes to the Stynes, Dean decides to take matters into his own hands. Sam tries to come to terms with his decision.