While looking for their father who has disappeared, demon hunters Sam and Dean start to investigate a bizarre string of murders in which husbands are being accused of killing their wives. The brothers head to a town in Missouri. While the suspects are the husbands and there's evidence that supports that they did it, all of them insist that they are innocent. Sam and Dean think that it might be the doing of their ikiryou (from Japanese mythology - a vengeful manifestation of part of a living person's soul) and start the investigation, however...

A couple gets into a car accident on a mountain road. When the wife, Molly, comes around, she can't find her husband anywhere and wanders about the forest where someone attacks her. By chance, Sam and Dean happen to pass by and she asks them for help. However, they are in the middle of investigating a ghost phenomenon which happened near the place of the accident.

Guided by Sam's vision, Sam and Dean return to the house where they spent their childhood. A mother and her child are being tormented by a mysterious phenomenon. The brothers think that it may be the doing of an evil spirit, so in order to find some clues they visit Missouri, a spirit medium who was close to their father. With the help of Missouri they succeed at exorcising the evil spirit. However, on the same night the mother and her child are once again attacked by a violent poltergeist phenomenon...

Sam and Dean were traveling in the Impala in the suburbs of New Orleans, when suddenly a police car starts chasing them. They are accused of being involved in a hit-and-run accident and causing a rear-end collision. The police arrest them without listening to their side of the story, but they are saved by Michael, the police chief's little brother and the vice-police chief, and are able to escape from the jail. However, hearing Michael mutter "the criminal might not be a human" piques their interest, so they decide to get in touch with him, but...

In a rural town a strange incident keeps occurring. Cows are being killed and their blood, sucked out. Hearing this, Sam and Dean decide to check it out. There, Dean meets a small boy named Ryan, who is being bullied. Dean sees his past self in Ryan and decides to teach him martial arts. In the meantime, Sam notices Jason, a coldhearted vampire hunter, and decides to keep an eye on him, but...

Three years ago, Sam said farewell to his life as a hunter with his brother, Dean, and his father, John, and went to a university to study law. There he met a girl named Jessica, who would later become his girlfriend. During that time, a mysterious incident happens to two of Jessica's friends: they die after bleeding from their eyes. The demon's hand draw's near Jessica's back, too. Meanwhile, as hunters, Dean and John are investigating the same incident.

Sam and Dean get a call from Bobby, a hunter friend of theirs, who tells them that he found some clues about their missing father. They meet up with Bobby whom they haven't seen for several years and he tells them about the mysterious death of Henderson, a hunter and friend of their father's when he was in the Marine Corps. Using the clues, the three of them start investigating who the criminal is and they soon discover that it's the same "demon" who killed their loved ones.

In the suburbs of Chicago, young females with blond hair and blue eyes are being targeted in a string of murders. Sam and Dean think that it may be connected to demon worshiping and during the investigation, find out that every 15 years over the past 50 there have been similar murder cases in various places. The case becomes even more mysterious when on the latest crime scene fingerprints are found of a woman who died in a car accident 50 years ago. In order to find out the truth, the brothers visit the husband of the woman, Richard, but...

While Sam and Dean are in Las Vegas trying to "earn some money", a chandelier falls down and kills the dealer right in front of their eyes. Since then, Dean is met with misfortune after misfortune. It turns out that Dean has been cursed by the God of Poverty, a Japanese god who is said to get attached to a human and cause him/her misfortune until their death. Can the brothers run away from the growing number of misfortunes?

Before the night of the full moon, prostitutes are being bitten to death by wild dogs, but this time a male lawyer was killed. Sam and Dean think that it may be connected to the werewolf legends and visit the victim's subordinate, Madison. Madison takes the place of Sam's now dead girlfriend in his heart and he decides to protect her, but she has a horrible secret.

Sam has a precognitive dream about a man dying and goes with Dean to a certain bar, but right before reaching him the man is attacked and loses his life. They are convinced that it was the doing of an evil spirit and visit the man's house. They meet his son, Max, and Sam feels like he has more than a simple connection to him. However, even though Max says that "they were very happy", the family seems to have a hidden secret.

While Sam and Dean are looking for their father, John is looking for clues about the being that killed his wife. He investigates Lily, the daughter of a woman who died in a fire in Michigan, the same way Mary had 22 years ago. Lily's father, Gray, tells him that on the day of the fire "a yellow eyed man" made Lily drink blood. They visit Lily, however "black eyed beings" are drawing closer to them.

Over the past few years, bizarre drowning accidents have been happening in a certain lake in Louisiana. They say the victims were attacked by a monster. Sam and Dean learn that, also in the past few years, the farming has been poor due to crop failure and a great number of the bees have died. They think that this is the doing of a demon and start investigating around the lake where the drowning accidents occurred. They find clues that show that it was the doing of a demon, but...

A series of bizarre murders occur in Colorado and a hunter named Daniel Elkins is among those killed. Sam and Dean think that it was done by a vampire and head out. Once there, much to their surprise, they find their father, John. Needless to say, the brothers are very happy and, following John's instructions, they set out to find the Colt, a gun stolen by the vampire that killed Elkins. Though Sam can't help but complain about the fact that John won't explain anything to them.

After Sam has a vision, he, Dean and John get into the car and set out. They finally have a chance to settle things with their old enemy, the "yellow eyed demon". However, John falls into a trap set by the demons and is captured. Can Sam and Dean save John? And will they be able to defeat their enemy, the "yellow eyed demon"?

The Winchester family suffered serious injuries during the fight with the demon. Sam and John regain consciousness, but Dean stays in a coma. Dean, whose soul was separated from his body, wanders around the hospital till he meets a Reaper. Dean is uncertain whether to die or stay in this world as a ghost and become the same as the demons they hunt. Meanwhile, Sam and John decide to take certain actions in order to save him.

Dean is tormented by the sin he committed and loses his reason to fight. When he can't take the suffering anymore, Missouri pays a visit and hands him a photo which awakens old memories inside him. 15 years ago, Ryle, a teacher at the school Sam and Dean were attending, became a mother like figure for the brothers and a member of the Winchester family. However, Dean remembers their mother, Mary, and can't idly accept Ryle. Ryle had a secret that even John didn't notice.

Leaving the words, "I'll be killed by the black dog!" behind, an architect jumps off his own mansion and dies. Sam and Dean think that it's possible that it's the work of their old demon enemy and start investigating the truth. They learn that 10 years ago, other geniuses died in similar ways. Sam and Dean think that the "Crossroads Demon", who grants people's wishes in exchange for their lives, is behind the case. In order to save the next victim, they take a big gamble and risk their own lives.

Jake, serving as a soldier in Afghanistan, lost his mother 22 years ago in a fire, just like Sam. The "Yellow Eyed Demon" follows him and tries to urge him to unleash his hidden power, but he always refuses to do it. While leading his troops, they are attacked by the enemy and on the verge of destruction. In order to save his friends who are falling in front of his eyes, Jake makes a decision. In the meantime, Sam and Dean visit Jake's hometown, Saint Louis.

Dean wakes up with an unknown woman next to him who turns out to be his wife. What's more, his mother Mary, who is supposed to be dead, is alive and Sam is married to Jessica, who was supposedly killed. Dean and the others gather together to celebrate his mother's birthday. Even though Dean was perplexed by this everyday life he started feeling happy, til he realized the truth behind that world and then...

When demon activity starts becoming more and more active, Sam suddenly disappears in front of Dean's eyes. When Sam comes to, he learns that Lily, Jake and other people who are holding special powers have been gathered together in a ruined ghost town. There, Sam and the others learn about their cruel fate and every detail about the dreadful plan imposed on them by the Yellow Eyed Demon.

After the fight between Jake and Sam, Dean has to make the ultimate sacrifice for his brother. Meanwhile the Yellow-Eyed Demon has his new servant and plans to unleash the hordes of Hell.