In an alternate reality mysteriously created as if Sam and Dean were never brothers and have never met, Sam and Dean work at a marketing office where they are forced to team up with one another when a series of mysterious suicides point to a ghost haunting the premises.
Sam and Dean are contacted by one Adam Milligan who claims to be John Winchester's son. The boys immediately suspect a demon trap and go to investigate. Adam turns out to legitimately be John's son and Dean is furious that John kept Adam's existence from them as well as sheltered Adam from the hunting life. Meanwhile other supernatural forces are at work, which lead to a tragic twist that neither Sam, Dean, or their new sibling could have guessed.
Castiel has been sent back to Heaven. His human host, Jimmy, tries to regain his life. But the demons won't leave him alone and now his family is at risk. Sam and Dean can help a little, but they're going to need a "miracle" to win.
Sam is becoming more and more inhuman. Dean and Bobby put him in the safe hold until he gets over his addictions. After Sam escapes with help, unknown to him, from Castiel, he finds Ruby and begins to feed once again. Dean begins to truly believe that the old Sam is gone for good.
When the last few of the 66 Seals are broken by Lilith's minions, Sam and Dean prepare for the big and probably futile fight in very different ways. Sam joins Ruby on a final attempt to kill Lilith before Lucifer rises, while Castiel and Zachariah tell Dean that it's time to play his part in stopping Lucifer.
In the aftermath of the Devil rising, Sam and Dean are whisked away and they are given a message from Chuck Shurley that Castiel is dead and that Luficer walks the Earth. As a result, Sam and Dean turn to Bobby for help to find a mystical weapon, called Michael's Sword. This will enable them to find the Devil before he takes on a new form to bring the slow end of the world. But the Winchester brothers are pitted against the archangel Zachariah who has plans for Dean, as well as more demons. Sam and Dean recognise a demon, Meg, who has returned from Hell.
An old friend of Bobby's calls, panicked about demons attacking his town. Sam and Dean arrive and everything appears exactly as they had expected. As time progresses they realize there is more than they bargained for.
Not sure he trusts himself, Sam decides to give up hunting and goes off on his own. But that night, a late-night visitor tells Sam that he won't let him off the hook that easily. Dean, intent on stopping the Apocalypse, continues hunting on his own and teams up with Castiel to find the Archangel Raphael since Castiel believes Raphael knows the location of God's vessel on Earth.
Dean awakens five years in the future in an abandoned city and is attacked by humans infected with a demonic virus that makes them mindless, flesh-eating zombies. Zachariah soon appears and explains to Dean that the world he sees is the result of his refusal to help the angels fight Lucifer.
Sam and Dean decide to start hunting together again and their first case leads them to a small town whose inhabitants are being killed by famous dead icons like Abraham Lincoln and James Dean, etc. Once they discover Paris Hilton has been involved in demonic crimes too, they don't know what to believe anymore.
Sam and Dean investigate a series of odd murders that strangely resemble fairy tales and urban legends. The brothers track down an 11-year-old boy named Jesse, and realize that whatever Jesse believes is coming true. Castiel appears again and tells Sam and Dean that Jesse is a serious threat and needs to be eliminated which deeply disturbs and divides them since it is against the Winchester brothers' custom of killing a human.
Sam and Dean discover that a witch is running a high-stakes poker game where the currency is life years vs. money. Bobby sees the game as a chance to get out of the wheelchair and bets 25 years, but loses. As Bobby begins to age rapidly, Dean steps in to save him but also ends up turning into an old man, leaving Sam holding the only hopes for their survival.
Sam and Dean catch up with the Trickster, who sends them through a dizzying montage of TV show parodies, inviting them to play along with their "roles" or be stuck in "TV Land" forever. But once Castiel shows up, the boys get an idea as to what the Trickster might be hiding and eventually come up with a surprising answer.
Dean and Sam are at a Supernatural convention where they meet lots of fans of the Supernatural Books. After a while they get the impression that something is not right at the location of the convention.