The Winchesters are taken to hospital and Dean is in a serious condition. While coma. He has an out-of-body experience, and is approached by a Reaper who tries to take his soul. She reveals that if he refuses to move on, he will one day become a vengeful spirit. Meanwhile, Sam tries without success to save his brother, so John contacts Azazel and offers to make a deal; in exchange for saving Dean’s life, he will give up his own life, his immortal soul, and the mystical Colt—a gun capable of killing anything. As the boys start life after the death of their father, they meet up with Ellen & Jo – friends of John’s. They discover that a Rakshasa—a demon of Hindu mythology— has been taking the form of a clown and tricking children into inviting it into their homes so that it can eat their parents. When not feeding, it takes the form of a blind knife thrower at the carnival; the brothers kill it with a brass pipe.
In Montana they then run into vampire hunter Gordon Walker(Sterling K. Brown), who Ellen warns them is dangerous. Sam is later captured by a group of vampires, and their leader Lenore (Amber Benson) reveals to him that they have reformed, feeding only on cattle. After being released unharmed, Sam tries to no avail to convince his brother that the vampires should be left alone. However, when they arrive at the vampire’s hideout, but Gordon is hell bent on killing them all. They try to convince Gordon not to kill her, but he cuts Sam’s arm to tempt the vampire. When Lenore resists the temptation, the brothers overpower him. As Dean ties Gordon up, Sam takes Lenore to safety. Jo joins them, against her mother’s & their wishes, to fight off the spirit of America’s first serial killer, H. H. Holmes in Philadelphia. We are also introduced to crossroads demons who grant you a wish and success for 10 years in exchange for your soul.
While investigating the viral infection of a group of violent people, Sam gets infected by the same virus. However, as a demon later reports, he turns out to be immune to it. Dean reveals that before their father died, he told him that he has to save Sam if he can, or else kill him. Sam meets a young woman, Ava, who has psychic visions just like him and he & Dean rescue her from Gordon, who goes to prison. Ava is later abducted by demons and her fiance is killed. They also narrowly avoid the clutches of FBI agent Henriksen while hunting a shapeshifter in a bank. Sam is possessed by the same demon that had taken over Meg and makes him kill a fellow hunter. With the help of Jo and an older hunter / family friend Bobby Singer, Dean is able to exorcize the demon out of Sam. After Sam and Dean have no luck in their investigation of several random urban legends coming to life on a college campus, they ask Bobby for help. He figures out that a Pagan trickster—a demigod capable of manipulating reality—is behind everything. They confront the janitor of the building near where the legends occurred, who reveals his true identity. The trickster tries to bargain with them, but the hunters attack him instead. He retaliates by conjuring minions to defend him, but in the end fakes his own death.
Sam will suffer more heartbreak after trying to save a recently turned female werewolf. They end up having an affair but she asks him to kill her as she is unable to be cured of the curse. They then head off to Hollywood to investigate the ghostly apparitions on the set of a horror movie. They then infiltrate a prison where a ghost of a former nurse is killing off inmates; they narrowly escape Henriksen & his men, thanks to a public defendant. Dean is attacked by a djinn, and suddenly finds himself in a world in which his mother had never been killed by Azazel. He and Sam were not brought up as hunters, and thus are no longer close. Although Dean enjoys his new life, a ghostly young woman seems to be haunting him. When he realizes that all the people that he and Sam had saved as hunters are now dead, he decides that he must give up his new-found happiness to save them. Though Sam does not believe him, he accompanies his brother to the djinn’s lair. There Dean discovers that the young woman he has been seeing is a victim of the creature. Noticing that she is alive but hallucinating—a way for the djinn to keep its victims captive while it feeds—Dean realizes that he, too, is within an illusory world. Dean forces himself awake as Sam rescues him in the real world, and kills the attacking djinn.
Sam is abducted by Azazel and left in a ghost town along with other psychic children—Andy Gallagher, Lily and Jake Talley. Sam is visited in a dream by Azazel, who explains that he has brought them together so that they can fight to the death, with the sole survivor becoming the leader of his army of demons. He also reveals why he killed Sam’s girlfriend Jessica, and shows Sam the source of the psychic children’s abilities—his own demon blood. Meanwhile, Ava uses a new demon-controlling ability, and forces an Acheri demon to kill Lily and Andy. She then reveals to Sam that she has been in the town since she went missing, killing off other psychic children that Azazel has sent there. She sets the Acheri demon on him, but Jake sneaks up behind her and uses his superhuman strength to break her neck, causing the demon to flee. Jake attacks Sam out of distrust, but Sam gains the upper hand and apparently knocks him unconscious. However, as Sam is distracted by an arriving Dean and Bobby, Jake regains consciousness and fatally stabs him. Sam dies in Dean’s arms.
Dean sells his soul to a crossroads demon in exchange for getting Sam’s life back. The demon gives him just 1 year to live on earth. Ellen later arrives at Bobby’s home, and gives them a map of Wyoming that Ash had left in the Roadhouse’s safe. Research reveals that Samuel Colt—creator of the Colt gun—created a giant devil’s trap using railway lines. At the trap’s center is an old cowboy cemetery, which Azazel forces Jake to go to. The hunters are there to meet him, but Jake subdues them long enough to use the Colt as a key to open a mausoleum. Sam then shoots Jake in the back, and finishes him off with multiple shots as he begs for mercy. As the mausoleum doors begin to open, they realize that it is a Devil’s Gate—a doorway to Hell. A rush of demons escape and break the iron railway lines of the devil’s trap, allowing Azazel to enter. As Ellen and Bobby try to close the gateway, Sam and Dean take the Colt to confront Azazel. Unfortunately, the demon catches them by surprise and takes the gun. He taunts Dean’s demonic pact and questions if what came back was “one hundred percent pure Sam”. Azazel prepares to kill them, but the escaped spirit of John grabs him. This distraction allows Dean to take back the Colt and shoot the demon in the heart, finally killing him. As Bobby and Ellen manage to close the gates, John’s spirit moves on.