Dean discovers that he has the crash... but is trapped as an ethereal spirit outside of his comatose body. He befriends someone else in a similar condition and tries to find a way to contact Sam and John. Meanwhile, John goes to extreme measures to save his son.
Sam and Dean receive a message on their father's cell phone from a woman named Ellen and head out to find her. They discover that Ellen is the owner of a roadhouse that serves as a meeting place for hunters. Meanwhile, a circus clown is targeting young children who will let him into their home so he can brutally murder their parents.
The brothers get the Impala running and head out to investigate a Montana case with cattle mutilations and decapitations. They end up teaming with Gordon Walker, a hunter whose motivation to destroy supernatural beings may be stronger even than theirs. Together they hunt a nest of vampires. Then Sam learns something about the vampires that might change everything and Ellen gives him some advice about Gordon.
While visiting their mother's gravestone, Dean notices a patch of cursed ground, and insists that a zombie is on the loose. Sam thinks he's just burying his grief for their mother, but Dean persists. The Winchesters eventually discover that someone has used necromancy to bring back a dead girl... but the zombie is seeking revenge on those who wronged her in life.
Sam gets another premonition of death, this time in Blue Ridge, Oklahoma. The brothers investigate and discover that Andy Gallagher is Sam's age and had a fire in his nursery when he was six months old. They soon realize that he has the power to control people, but Dean isn't convinced that Andy is responsible for a recent string of suicides.
Blond women have disappeared from an apartment building for 80 years. Jo gives the file to the Winchesters after her mother Ellen refuses to let her investigate. However, she defies her mother and joins Sam and Dean in the field, and they discover that the ghost responsible is the spirit of of H. H. Holmes, America's first serial killer, is behind the murders.
Sam and Dean travel to the scene of the murder of a lawyer and his wife who claimed to had seen a ghost prior to their deaths. But Sam and Dean don't get far when local authorities come across the brothers' record and arrest them for a double homicide. However, when the ghost begins to visit detective Ballard, the woman that arrested the brothers, she begins to think that Sam and Dean's story might just be true and she might be next.
Two miraculously successful individuals die after claiming to be haunted by hell-hounds. Sam and Dean discover that each of them visited a bar where a demon has been making people's dreams come true in exchange for their souls. They find the last person and Sam protects him while Dean summons the demon. However, he is shocked when it reveals the truth surrounding his father's death, and tempts Dean into getting the one thing he wants the most - his father.
Sam has a vision of Dean killing a demon-possessed man. The brothers travel to River Grove, Oregon to find answers to Sam's premonition, and discover a virus-stricken town where the victims are driven to kill. Sam is infected by the virus and prepares for his deadly fate, but proves immune so Dean decides to tell Sam the truth about what John told him before he died.
When Dean tells Sam about what John told him before he died, Sam heads off to Indiana without Dean knowing. There Sam meets Ava Wilson, a psychic who was looking for Sam in order to warn him about his fate. Meanwhile, Dean tracks down his brother and discovers that hunter Gordon Walker plans to kill Sam, believing he's a monster.
At a small Connecticut inn, Sam and Dean encounter a single mother, Susan, whose daughter, Tyler, often plays with an imaginary friend. As Susan and Tyler are packing to move after selling the run-down Pierpont Inn, Sam and Dean begin to notice strange dolls with backward heads, an urn with a hoodoo pattern, and a mysterious old woman confined to the attic. Tthe brothers soon discover that the imaginary friend may be the ghost behind recent deaths of people living in the rural Connecticut town.
Sam and Dean investigate a string of robberies with disturbing similarities. In each robbery, a top-notch employee holds up and robs the business and then commits suicide. The Winchesters discover that a shape shifter is at work and try to get ahead of it at the next business it intends to hit: a bank.
The Winchester brothers look into the murders of several people who say they were visited by an angel and were simply carrying out God's will. After further investigation, Sam and Dean find that those murdered were guilty of secret crimes, but the brothers split on what they think the truth is - Sam believes that there is an angel that caused the murdered, but Dean thinks that a demon is the cause of the deaths. However, Dean soon changes his belief when he sees the unexplainable.
A missing Sam finally makes contact with Dean, who travels to his younger brother and discovers he has no memory of the last few days... and he's covered in blood. As they retrace Sam's step, Sam begins to believe that his dark side has finally taken over.
Sam and Dean investigate a series of urban legends coming to life on a college campus. When they start arguing incessantly, they have no choice but to call in Bobby for help.
Sam and Dean come to the aid of a woman, Molly, who claims that her car went off the road after encountering a ghost. There's no sign of the car, and the brothers take Molly along to hunt down the ghost, as it becomes clear that their encounter with Molly isn't random chance.
While investigating the mysterious death of a lawyer who appears to have been mauled to death by an animal, Sam and Dean realize that they are tracking a werewolf. As they look into the death, Sam becomes attracted to Madison, the victim's secretary, and when it appears that Madison will be the next victim, Sam does all he can to protect her.
While in Hollywood taking some R&R, the brothers investigate the mysterious death of an actor who was killed on the set of a horror film. Rumors begin to fly that he was killed by a ghost, but Sam and Dean soon find that the death was a publicity stunt. However, when a studio executive and the film's producer are found dead, Sam and Dean realize that the rumors about a haunted set may be true.
When a ghost begins killing off inmates one by one at prison, Sam and Dean let themselves get captures so they can go into the penitentiary to investigate the deaths from the inside. However, when FBI agent Henricksen takes over the murder cases, the brothers soon find that getting out of the prison may be more difficult than finding the murderous ghost.
While on the trail of a Djinn, Dean wakes up one night and finds that he is in an alternate reality where Mary never died and John Winchester and his sons never hunted monsters. In this life, Sam is in law school and engaged to Jessica, and Dean has a steady job and a beautiful girlfriend. However, when a strange woman begins following him around , Dean realizes that all of the people that he and Sam saved have died, and has to decide if he wants to stay in his new life or return to reality.
Sam is kidnapped by the Yellow-Eyed Demon and finds himself trapped in a ghost town along with other children with special abilities much like his own. Sam and the others who have been abducted soon find out that the Yellow-Eyed Demon has brought them together in order to determine which is the most powerful. The Yellow-Eyed Demon shows Sam the truth behind the death of one of his parents. Meanwhile, Dean and Bobby team up to help save Sam before the battle breaks out, but, unfortunately, are too late.
Dean refuses to accept Sam's death, and makes a painful sacrifice to bring him back. Meanwhile, the Yellow-Eyed Demon uses Jake to advances his master plan to take over the Earth and Sam and Dean must track him down before it's too late.