The prize: ending the Apocalypse. The price: Sam's life. Season 5's horrific finale left Dean alone, as Sam descended into Hell. Now a different man, Dean vows to stop hunting and devote himself to building a family with Lisa and her son Ben. Then, mysteriously, Sam reappears, drawing Dean back into the old life. But Sam's a different man too. He's returned without his soul. How the Winchesters confront this greatest challenge yet to their powerful bond is the troubled heart - and soul - of the profound and thrilling 22-Episode Season 6. As the brothers struggle to reunite, they must also battle deadly supernatural forces. Demons. Angels. Vampires. Shapeshifters. And a terrifying new foe called the Mother of All.
Sam is mysteriously released from Hell and seeks out his brother, trying to have a normal life. Together the brothers must join forces with their maternal grandfather, Samuel, and begin the fight anew.
Sam investigates a case about missing babies whose parents are being murdered. At one of the crime scenes, he discovers a baby that was left behind and calls Dean for help. Reluctant to leave Lisa and Ben, Dean finally agrees to meet Sam and surprises his brother with how parental he has become. The brothers take the baby to Samuel, who decides to raise it as a hunter, which infuriates Dean. However, before they can decide the baby's future, a shape-shifter breaks in and attempts to kidnap the baby.
Sam and Dean call Castiel for help when they investigate a case about several dead police officers who seem to have been killed by the plagues of Egypt. Castiel confirms the staff of Moses was used to kill the cops and tells Sam and Dean that Heaven is in a state of chaos and God's weapons have been stolen. The three head off to find the thief and come face to face with an old enemy.
After Bobby discovers Crowley has no intentions of returning Bobby's soul, the hunter takes matters into his own hands. He calls on Sam and Dean for help after he unearths one of Crowley's deepest secrets. Meanwhile, Sam and Dean learn what Bobby does all day when they are not around.
After a group of young girls go missing Sam and Dean realize that a group of vampires have taken up residence in the small town. After a fight with two of the blood-suckers, Dean is bitten and turns into a vampire. Samuel tells Dean he can change him back but he’d have to get the blood of the vampire who turned him. Dean infiltrates the nest and runs into the Alpha...
Sam and Dean investigate a series of suicides and discover the victims were being told brutal truths that drove them crazy. They find out someone is invoking the Goddess of Truth, Veritas, forcing people to be cruelly honest against their will and Dean is the next victim. Dean is forced to tell Sam the truth about how he feels about his return from Hell.
Dean becomes suspicious of Samuel's motives, but Sam isn't sold on the idea that their grandfather is doing anything wrong. The brothers go along on a hunt with Samuel and the other Campbells, but things go terribly awry.
Dean and Sam investigate what seems to be a werewolf killing but turns out to be a skinwalker posing as a family dog who is taking revenge on his owner’s enemies.
While Sam and Dean are investigating a UFO sighting, Dean is abducted from a crop circle. However, when he awakens, he discovers he isn't dealing with aliens, but fairies! Unfortunately, only Dean can see the fairy that keeps attacking him which makes tracing and stopping them difficult. The brothers become even more perplexed when Sam's investigation leads them to a world full of elves, gnomes and a leprechaun.
Meg kidnaps Sam and Dean and tries to force them to tell her where Crowley is hiding. Sam makes her a deal - they will help her find Crowley if she promises to torture him for information about how to get Sam's soul back. Castiel joins the fight but finds it difficult to work with Meg.
Dean seeks out Death to help get Sam's soul back. Death tells Dean he will help Sam if Dean will agree to act as Death for 24 hours. Meanwhile, Sam decides he doesn't want his soul back and asks Balthazar for a protective spell to keep his soul out of his body. Balthazar tells Sam he needs the blood of his father for the spell to work and since John Winchester is dead, Sam decides Bobby is the next best thing.
Dean and Bobby anxiously wait for Sam to wake up to see if Death was able to restore his soul without causing Sam to lose his mind. Meanwhile, Dean and Bobby investigate a disappearance of virgins and discover dragons are behind the kidnappings. Bobby sends Dean to a doctor who owns the only weapon in the world that can slay a dragon, but Dean must prove himself worthy enough to take it
Sam starts to have flashbacks to a case he worked on with Samuel before he reconnected with Dean. Sam receives a mysterious text with coordinates to a small town, so the brothers decide to investigate. Dean is surprised when the townspeople start telling him some of the things Sam did while he lived there.
Ben calls Dean and tells him Lisa is in trouble. Dean leaves Sam to investigate a case alone and rushes home to rescue Lisa, however, he’s not prepared for what meets him at the door. Meanwhile, Sam discovers the men that were murdered were all a part of a cruel practical joke played on a female co-worker who went missing.
Dean and Sam find themselves in an alternate reality where everyone believes they are two actors named Jensen Ackles and Jared Padalecki, who star in a TV show called Supernatural about two brothers who hunt monsters.
Eve, the Mother of All, unleashes a new monster upon the world: a black worm-slug that can enter the brain and force people to kill. Sam and Dean join forces with Bobby and Rufus and track it to a cannery, only to discover that Gwen and Samuel are also there looking for the monster... and none of them know who the monster is inside.
After Balthazar changes history and keeps the Titanic from sinking, Fate intervenes and begins killing those that would have died on the ship. Castiel tells Sam and Dean that Fate is very upset with the two of them and the only way they can stay alive is to kill her.
While searching for a way to defeat Eve, Dean stumbles upon Samuel Colt’s journal in the Campbell library. Realizing Samuel might have the answer to their problems, Sam and Dean ask Castiel to send them back in time so they can meet the man himself. While Sam is a bit reluctant to time travel, Dean is beside himself with excitement to return to the Wild, Wild West.
Sam, Dean, Bobby and Castiel track Eve to a small town in Oregon. The guys discover the townspeople have been converted to demons, but surprisingly, they all appear to be dying. When they finally do meet Eve, she decides to torture the brothers by bringing back their mother.
Castiel tells Sam, Dean and Bobby about the war in Heaven and how he and Raphael became enemies. Bobby believes Castiel is hiding something, but Dean refuses to believe it.
The wall comes down in Sam’s head and all hell breaks loose. Dean and Bobby are, for once, at a total loss on how to help him and are forced to stand by and do nothing while Sam breaks. The battle for heaven comes to a head.
