|Greenwood Mississippi, August 1938. A man is playing blues music on his guitar in a bar, called Lloyd's. He stops and starts the music when something can be heard outside, and a shadow flies past the window. The guitarist leaves the bar and runs from the sound of dogs barking, dropping his guitar and hiding in a barn, while the dogs bang against the door. Some of the bar’s patrons get into the barn, and the man dies in their arms.
Back in the present, Sam tells Dean that he’s in the FBI’s database. Nothing has been posted on Sam, and Dean teases him for being, a “harmless, innocent young man.” They start discussing a case of an architect (Sean Boyd) after jumping off a building he designed. He’d previously called animal control after seeing a black dog, but no-one else had sighted it. Posing as two men from Architectural Digest, looking to write a tribute to Sean Boyd, Dean and Sam interview Boyd’s business partner. Apparently approximately ten years ago, Boyd had been a bartender at Lloyd's. Then overnight he’d practically become a genius in the field.
Outside the Animal Protection Agency, Dean joins Sam in the Impala, and shares the information he got from the secretary, including all the calls about black dogs and the secretary’s MySpace address (though Dean has no idea what it is). Dean and Sam, look for Dr Silvia Growman, who was one of the calls for a black dog. She had left previously, so the brothers talk to the maid, who doesn’t know where she had been. The doctor became the Chief surgeon at a hospital ten years before, and Dean finds a picture of Silvia at Lloyd's bar. In a hotel room, Silvia pays for another night to a worker who’s face distorts when she looks at him.
Sam and Dean make it to Lloyds bar, and Dean spots the a plant used in summoning rituals, where there is a crossroads. They dig in the center and find a tin containing a photo of a man. They realise that the black dogs are hell hounds collecting souls after deals are made with a demon. Back in her hotel room, Silvia is attacked and mauled to death by an invisible dog.
Rosedale, Mississippi 1930, a man buries a bag in a crossroads, and a demon appears. He asks to be the greatest blues man that ever lived. They kiss to seal the deal, and when the man opens his eyes again, the demon has gone.
In the present, Dean and Sam talk about Robert Johnson’s music, which Dean explains the occult references about crossroads and hell hounds to Sam. The story went that he died muttering about black dogs. Dean doesn’t want to rescue them, but Sam is shocked. The brother’s go to find the man in the original photo, George Darrow. He’s living in a rundown old house. They find something like pepper in a line outside the door. It opens, and George Darrow lets them in, after Dean produces the photo. In the apartment, the walls are covered with paintings. It turns out that the substance by the door was goofer dust (voodoo), not pepper. George gives them a bag. He admits that he called the demon, and didn’t want their help. He tells them that it wasn’t worth it because he asked for talent, and not fame. There were three others that made deals. The architect, the doctor and a man named Evan Hudson. He sends them away, because all he wants to do is finish his last painting.
Evan Hudson is working in an office when he hears the sound of the hell hounds outside. He says goodbye to his wife, who thinks he wants her out of the house. Just before she leaves, she looks back at him she looks back and her face distorts. Dean and Sam knock on the door, and Dean starts interrogating him, before Evan realises why they’re there, slams the door and runs. Dean kicks it open and they catch up with him. Sam explains that they want to help, but Dean is cynical and taunts Evan by asking why he made a deal, until he realises that Evan saved his wife from certain death. Dean reacts badly to this. He asks Evan what Julie would have thought? He accuses Evan of doing it for himself, and reminds him that Julie would have to live without him. Sam pulls Dean into the corridor. Dean wants to go back at summon the demon while Sam protects Evan, but Sam confronts him. He voices the thought that John made one of these deals to save Dean’s life. Dean agrees and leaves.
Back at the crossroads, Dean buries a box and demon appears behind him. She claims to know all about him, and Dean tries to get the demon into the Impala, but she spots the devil’s trap underneath and gets angry. Meanwhile, Sam makes a circle of the goofer dust. Dean wants to release Evan Hudson from his contract, in exchange for him. The demon comments that he’s like his father, and confirms his theory that John did make a deal. Elsewhere, the hell hounds have started to come for Evan. The demon advances on Dean, who manages to trap her under another devil’s trap. She taunts him with his father, and offers him his father back in return for Dean’s soul. Once trapped, Dean wants to make a deal. He offers to let her out in return for Evan’s soul. Pulling out a book, he begins an exorcism.
The hell hounds make it into the room with Sam and Evan, the wind starting to break up circle and they have to run whilst Dean continues to chant. The demon appears to be in pain, and gets him to stop, finally agreeing to the demands. Evan is left safe. True to their deal, Dean breaks the devil’s trap and let’s her out. She laughs and tells him that John is suffering in hell for him, and that Dean should have taken her deal when she offered. Before he gets a chance to say anything else, the demon leaves the body it’s possessing. Driving in the Impala, with blues music playing. Dean wants to know how he’s supposed to live with what their father did, he reckons he should have gone out fighting. But Sam argues that people like Evan Hudson are alive because of John. Sam asks if Dean was ever tempted to make the deal.
Dean remains silent and looks away, changing the music back to rock.