Sam and Dean have spent the last year cruising the highways of the United States, searching for their lost father and encountering creatures. Finally, they found their father, just as he was closing in on the Demon who claimed their mother.
Sam (Jared Padalecki), Dean (Jensen Ackles) and John (Jeffrey Dean Morgan) were left for dead after the Demon plowed a semi into the Impala.
Now, one of the Winchesters hovers between life and death as the surviving family must face an old and powerful adversary.
Sam (Jared Padalecki) and Dean (Jensen Ackles) listen to a message on John's (Jeffrey Dean Morgan) cell phone from a woman named Ellen (guest star Samantha Ferris) and decide to track her down.
They are shocked to discover Ellen runs a road house that also serves as a gathering place for hunters like themselves. Meanwhile, at a small town carnival, a clown is persuading children to let them into their home so he can murder their parents.
Sam (Jared Padalecki) and Dean (Jensen Ackles) meet Gordon (guest star Sterling K. Brown), a fellow demon hunter who has been systematically killing vampires in a small town, and Dean immediately bonds with the older man.
However, after Sam meets with the lead vampire (guest star Amber Benson) and discovers they are actually peaceful creatures who survive on cattle blood, he decides not all supernatural beings are evil and forces Dean to choose whether he will side with Sam or Gordon.
Dean (Jensen Ackles) and Sam (Jared Padalecki) investigate the murder of a college student (guest star Summer Glau) who has come back from the dead seeking revenge on those who mistreated her while she was alive. Upon confrontation, the ghost savagely attacks Sam, leaving him injured.
Sam (Jared Padalecki) and Dean (Jensen Ackles) meet Andy (guest star Gabriel Tigerman), a slacker who has psychic powers of persuasion, which he uses to gain favors from people. However, when some of Andy's friends start dying, the brothers question whether Andy is using his powers to kill.
After learning that Andy's family was visited by the Demon 22 years ago, Sam wonders if Andy is part of the group of children the Demon told him about, and if that means he himself will eventually turn evil.
Sam (Jared Padalecki) and Dean (Jensen Ackles) investigate the brutal slayings of blond women from an apartment building and discover the demon responsible is the ghost of the first serial murderer, H. H. Holmes.
Meanwhile, defying her mother's (guest star Samantha Ferris) wishes, Jo (guest star Alana Tal) follows the Winchesters on their hunt and ends up getting captured by the ghost and buried alive.
Sam (Jared Padalecki) and Dean (Jensen Ackles) investigate the murders of a lawyer and his wife who claimed to have seen a ghost right before they died. However, after local detectives Ballard (guest star Linda Blair) and Sheridan (guest star Jason Gedrick) uncover the Winchesters' records, they arrest the brothers for a double homicide before they are able to find the ghost.
When the ghost begins to visit Ballard, she begins to wonder if the tale Sam and Dean are telling her could be true, and if she might be the next to die.
When two highly successful professionals die after claiming to be haunted by hellhounds, Sam (Jared Padalecki) and Dean (Jensen Ackles) investigate the local dive bar and discover it sits upon a site where a deal-making demon has been making people's dreams come true in exchange for their souls.
Dean summons the demon to exorcise it but is horrified after it reveals the painful truth about John's death and tempts Dean by offering him the one thing he wants more than anything - his father.
After Sam (Jared Padalecki) has a vision of Dean (Jensen Ackles) killing a young man who seems to be possessed by a demon, the two brothers head off to Oregon to search for answers.
They come across a town infected by a deadly virus that drives a person to kill. Sam becomes infected by one of the locals and prepares for his deadly fate, but after nothing happens to him, Dean decides to come clean and reveal what John (Jeffrey Dean Morgan) whispered to him before he died.
After Dean (Jensen Ackles) tells Sam (Jared Padalecki) what their father told him before he died, a distraught Sam sneaks off to Indiana without Dean. While there, Sam runs into Ava (guest star Katherine Isabelle), a psychic who confesses to Sam she sought him out to warn him of his impending death.
Dean discovers Gordon (guest star Sterling K. Brown) is after Sam and races to find his brother in time to save him.
Sam (Jared Padalecki) and Dean (Jensen Ackles) investigate two strange deaths at a small Connecticut inn run by a single mom (guest star Annie Wersching) whose young daughter (guest star Matreya Fedor) plays with an imaginary friend.
The brothers find evidence of voodoo around the inn, but soon realize the little girl's imaginary friend may in fact be a demon who is killing the townspeople.
Sam (Jared Padalecki) and Dean (Jensen Ackles) investigate a string of robberies with a disturbing pattern, in each incident a trusted employee holds up the bank then commits suicide.
However, when the autopsy reports shows their actual time of death as several days before the robbery, Sam and Dean realize the shape-shifter has returned.
Sam (Jared Padalecki) and Dean (Jensen Ackles) investigate the murders of several people by individuals who claim they were visited by an angel and were carrying out God's will.
After the brothers learn those murdered were actually guilty of secret crimes, Sam begins to believe this angel really does exist, but Dean stands firm on the fact a demon is behind the slayings - until he sees something even he can't explain.
After receiving a frantic call from Sam (Jared Padalecki), who has been missing for over a week, Dean (Jensen Ackles) races to his brother's side. He finds Sam covered in blood, but unable to remember anything that happened.
Upon investigation, the brothers are horrified to discover a tape that shows Sam killing another hunter in cold blood, causing Sam to believe his evil side is finally taking over.
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Sam (Jared Padalecki) and Dean (Jensen Ackles) call upon their family friend and fellow hunter Bobby (guest star Jim Beaver) for help after they are stumped by violent and unexplainable happenings on a local college campus.
Bobby arrives with a suspicion as to the culprit behind the killing spree and the brothers' escalating feud.
While driving down a deserted road, Sam (Jared Padalecki) and Dean (Jensen Ackles) are startled after a bloody woman named Molly (guest star Helfer) bolts out in front of the Impala screaming for help from the crazy farmer (guest star) who is chasing her.
Sam and Dean investigate and discover the man is actually an angry spirit who kills one person the same time every year and has decided Molly will be his next victim.
After investigating the death of a lawyer (guest star David Quinlan) who appeared to have been killed by a wild animal, Sam (Jared Padalecki) and Dean (Jensen Ackles) realize they are tracking a werewolf.
Sam is immediately attracted to the lawyer's secretary Madison (guest star Emmanuelle Vaugier) and when it seems as if Madison will be the werewolf's next victim, Sam offers to stay overnight to protect her. Dean heads out to hunt the animal and is stunned by what he finds.
Sam (Jared Padalecki) and Dean (Jensen Ackles) make a trip to Hollywood to investigate the death of one of the actors on a horror film set after rumors begin that he was killed by a ghost.
They discover the death was a publicity hoax but when the executive producer and a studio executive are killed, Sam and Dean realize they are dealing with a haunted set.
After hearing about a ghost that has been killing off inmates one by one, Sam (Jared Padalecki) and Dean (Jensen Ackles) decide the best way to investigate this spirit is from the inside and allow themselves to get thrown into the state penitentiary.
However, after FBI agent Henricksen (guest star C. Malik Whitfield) shows up to take over their case, getting out of prison becomes a bigger challenge than finding the spirit.
While hunting a Djinn, a genie, Dean (Jensen Ackles) is attacked and transported to a world where his mother (guest star Samantha Smith) is alive, Sam (Jared Padalecki) is in law school and engaged to Jessica (guest star Adrianne Palicki), and Dean lives a very normal life with his girlfriend (guest star Michelle Borth).
However, after he starts seeing a strange girl (guest star Melanie Neige Scrofano) and learns all the people he has saved in the past have died, Dean must decide whether he wants to stay in this new safe life where everyone he loves is alive or if he should return to the hunt.
Sam (Jared Padalecki) is abducted by the Yellow-Eyed Demon and finds himself in a ghost town with other children who have special abilities. They learn the Demon has brought them together to initiate his endgame: an all-out war against the human race.
In an effort to encourage Sam to fight, the Demon shows him what really happened to one of his parents.
Dean (Jensen Ackles) enlists Bobby's (guest star Jim Beaver) help to find Sam before the battle begins, but he arrives too late.
Dean (Jensen Ackles) must deal with the aftermath of the fight between Sam (Jared Padalecki) and Jake (guest star Aldis Hodge) and pays a steep price for his involvement.
The Demon and his spirits threaten to overtake the hunters until they receive help from an unexpected ally.