Season 6 starts off a year after the end of the last season with Dean who now lives with Lisa and her son Ben, and having given up hunting for a year after Sam jumped into Lucifer’s Cage. When mysterious occurrences start attacking Dead, he is rescued by Sam. Sam tells Dean he escaped from Hell around the time Dean started living with Lisa, but is unsure of how, and introduces Dean to family members he never even knew existed: the Campbells; his mother’s cousins, hunters led by none other than their grandfather Samuel. They go to destroy a Djinn who is attacking people close to the brothers and once that is done Dean stays with Lisa & Ben while Sam joins the Campbells. Their lives will come together very shortly as Sam asks Dean for help in a case about missing babies whose parents are being mysteriously murdered and Sam finding one baby left behind. However, before they can decide the baby’s future, a shape-shifter breaks in and kidnaps the baby. The shape-shifter was apparently the father of all shape-shifters (the alpha), and was much stronger than the others. Samuel secretly talks to someone on the phone promising he’ll capture the alpha. After losing the baby, Dean returns to Lisa, and tells her that he is not sure whether he should stay to protect her and Ben, or go to make sure nothing happens to them. Lisa tells Dean to leave, but just come back home whenever he can.
This season introduces the recurring character of Balthazar (Sebastian Roche) an angel who has deserted heaven to live on earth, indulging in whatever he pleases and he gave the staff of Moses to a human. When Gabriel arrives to retrieve the staff, Balthazar initially leaves but comes back to destroy Gabriel’s human host body. He then tells them that Heaven is in a state of chaos and civil war between angels and God’s weapons have been stolen. Meanwhile Dean begins to notice the change in Sam. Bobby summons Crowley to get his soul back who reneges on the deal and holds it for a ten-year period. Sam & Dean go to Crowley’s remains in Scotland and threaten to burn it if he doesn’t give Bobby’s soul back, which he reluctantly does. Sam’s change is evident when he allows Dean to be turned into a vampire, supposedly to help them find the vampire nest and kill them off. But it is when the Goddess of truth fails to put a spell on Sam, Dean has confirmation that Sam is not who he seems to be – Sam says he can’t sleep or feel emotions. Castiel finds out that Sam’s soul is missing and in the investigation they learn that Samuel is working for Castiel hunting alphas and that the demon lord of hell is the one who rescued Sam. The brothers reluctantly now have to help Samuel & Crowley capture monsters. A leprechaun senses the lack of a soul in Sam and makes an offer to get it back for him, but Sam declines and attacks him instead, telling Dean that deals aren’t a good thing.
Meg & her followers, who remain loyal to Lucifer, become cagey allies against Crowley, who admits he can’t get Sam’s soul back. He is seemingly destroyed by Castiel burns his remains. Dean makes a deal with Death to get Sam’s soul from hell and he does, pushing it into a screaming & pained Sam – but builds a wall around his memories. Sam wakes up normal, not remembering the things he did without a soul, which Castiel tells him about. Sam & Dean have to stop some dragons from opening Purgatory and releasing something known as ‘the Mother of all’ – Eve. Sam will soon be confronted by some of the things he did soulless & working with Samuel. Balthazar gives Sam a key and sends the brothers to an alternate reality where they are known as Jared Padalecki and Jensen Ackles. Sam and Dean discover that everyone they knew in their reality is an actor in this reality: Castiel is a Twitter-addicted nice guy named Misha, and Sam is married to ‘Ruby,’ Genevieve Padalecki. Sam and Dean attempt to return to their reality, but are hampered by their alternate lives as actors and the crew of their TV show. One of Raphael’s assassins, Virgil, arrives to kill them, but fails; eventually, the brothers beat him. They are then pulled back into their own universe and confronted by Raphael (in a new female vessel). Balthazar and Castiel appear and reveal that the key was a ruse to divert Raphael’s attentions from the real transaction: Castiel now owns the weapons of Heaven that Balthazar stole. Frustrated with Castiel, the brothers ask why he did what he did, to which Castiel simply states that he will tell them another time.
Samuel is infected by a worm sent by Eve and is killed by Sam and Rufus is also killed. The brother then must undo Bathazar’s work – he went back to 1912 & prevented the Titanic from sinking (to avoid the movie & Celine Dion’s hit single from being made), causing one of the Fates sisters Atropes to go on a killing spree of all the survivors descendants. The brother then travel back in time to 1861 in Wyoming to kill a phoenix and collect it’s ashes – as that can kill Eve. They catch up with Eve tells Sam and Dean that Crowley is still alive and is after the power of the souls, not the purgatory and is also torturing her children. She takes the form of Mary to show them what is mother’s love. Her plan is to ruin Crowley’s plans by sending souls to Purgatory instead of Hell (only monsters go to Purgatory). Dean refuses to deal, and Eve tries to turn him, but he drank whiskey mixed with phoenix ashes earlier, which poisons her. Sam, Dean and Bobby argue because they are suspicious of Castiel, thinking he let Crowley live. Crowley meets with Cas at the diner, saying he is tired of covering up his messes. It is then revealed that it was actually Cas who pulled Sam from hell. Castiel goes to meet with Crowley who is doing experiments with Eve’s corpse. Cas reveals he started the civil war in Heaven, using 50,000 souls from Hell, because Raphael wanted to raise Michael and Lucifer and resume the Apocalypse. The brothers summon Castiel and trap him in a circle of holy fire. Dean asks if Castiel is working with Crowley, and from Castiel’s inability to look him in the eyes, Dean knows the answer. ack at Bobby’s, Castiel appears to Dean, telling him to understand that he is doing this for him. Dean asks him to trust him and stop what he is doing, because he’s like a brother to him, but Castiel says he won’t. Dean then says he will do anything to stop him. Castiel asks God for a sign to see if what he is doing is right or wrong, and says that if God doesn’t answer him, he will do whatever it takes. There is no sign.
Crowley kidnaps Lisa & Ben and has a demon posses her so Dean must exorcise her. Lisa is mortally wounded however and as Dean grieves as she lies dying, Castiel appears to help. As a final act of friendship with Dean, he heals Lisa’s wounds without being asked and both he and Dean admit they wish this changed the fact that they are now enemies. As one last favor to Dean, Castiel erases Lisa and Ben’s memories of Dean so they can live a safe, normal life. Castiel shows up and breaks the wall in Sam’s mind when they refuse to stop trying to stop him. In the real world, Balthazar betrays Castiel by giving up Crowley’s hiding place to Dean and Bobby. Castiel discovers Balthazar’s treachery and kills him. Dean and Bobby arrive at Crowley’s hideout but are attacked by a cloud of demons. Furious, Castiel tries to kill Crowley but discovers that he cannot. Crowley has allied with Raphael as Castiel betrayed him. Giving up a Purgatory being’s blood, Castiel escapes, while Crowley recites the spell to open Purgatory with Raphael. Dean and Bobby recover and storm in but are both easily beaten by Crowley. As Crowley finishes the spell, nothing happens. Castiel had switched the jars of Purgatory blood, using the real one to open Purgatory and absorb every soul there. Now all powerful, Castiel destroys Raphael, while Crowley escapes. A recovered Sam arrives and stabs Cas with an angel’s sword, but it has no effect. Castiel proclaims himself as the new God of the world, and tells the group to bow down and profess their love unto him their Lord or he shall destroy them.