At a young age, Sam and Dean Winchester witnessed the unexplainable death of their mother, which in turn led their father to teach them skills which could be of use in the search for whatever it was that took her life.
Sam and Dean follow clues from their father's journal and end up deep in the woods, where they try to learn what happened to several campers gone missing. It soon becomes apparent that the brothers are facing down a Wendigo, in Native American lore a human-turned-creature who has gained strength by consuming human flesh.
Sam and Dean look into a number of drownings that were labeled as suicides and learn that a young boy with a power of underwater travel is bringing certain residents of the local town to justice for a long-gestating secret. Dean, meanwhile, begins to forge a connection with a boy who may possess the power of second sight.
When the spirit of The Phantom Traveler causes a plane crash which leaves only five passengers alive, Sam and Dean must head into the skies themselves in order to rid them of the angry spirit, who may next otherwise pursue the five survivors.
A group of teenagers in Nebraska unleash a set of murderous spirits after a dare forces one of the teens to chant “Bloody Mary” into a mirror. Sam and Dean must try and stop other teens from bringing Bloody Mary into the world when they realize she can move through any surface that is reflective.
A college friend of Sam’s is accused of murder, prompting Sam and Dean to investigate. After the brothers learn that a shapeshifter with the ability to adopt human likenesses has committed that and other murders, they are forced to end its reign of terror before it, having now taken on Dean’s likeness, kills again.
An Iowa town is terrorized by the spirit of the infamous “Hook Man,” but when Sam and Dean learn that his murders all somehow revolve around the town minister’s daughter, they are forced to rid the world of the Hook Man’s skeletal remains.
Sam and Dean investigate the death of a man by insects that dug into his brain while he was working on a construction site. When the brothers discover that the construction site is formerly sacred Native American soil, they are forced to stop an impending bug onslaught that is part of the tribe's cursed retribution.
Sam and Dean decide to revisit their childhood home based on a recurring dream of Sam's. Upon arrival, they learn that the woman who now lives there with her two kids has been having the same dream as Sam. The two brothers decides to enlist the help of a psychic mentioned in their father's writings to combat the angry spirits inside the house, all the while coping with the death of their mother that took place there.
Sam and Dean investigate an old sanitarium whose members once led an uprising against the cruelty of its main doctor. In their quest to find four missing college kids on the premises, the inmates' spirits work their spell and pit brother against brother.
Sam and Dean are rebuked by their father after finally receiving word from him. Sam continues to go after him, while Dean obeys his wishes to carry out another ghost-chasing gig in Indiana, one in which couples mysteriously vanish on the same date every year. Dean's investigation leads him to discover a ritual sacrifice by a town of farmers. Meanwhile, Sam picks up a hitchhiker on the way to California with secret ties to the demon world.
Dean gets electrocuted while trying to fight off a demon, but when he is told he has serious heart damage and only months left to live, Sam races to find a supernatural cure that could help him. Dean's salvation, however, a preacher with healing powers, may be in leagues with death himself.
Dean's first girlfriend, Cassie, asks him to head down to Mississippi and look into a string of racially-tinged killings. As Sam and Dean travel down and get involved in the case, in which ghost-driven trucks are somehow involved in each death, Sam begins to think that Dean is not quite over his love for Cassie.
Sam coaxes Dean onto a case that came to him in a dream, in which a man's murder is disguised as a suicide. They soon find out that the victim has a son with telekinesis, and he has been using his newfound powers to enact murderous revenge on his abusive relatives. Details of the case also provide some new insights into the murder of Sam and Dean's mother years earlier.
A Minnesota man vanishes into the air, and a young boy saw it all happen. When Sam and Dean investigate, Sam is snatched, but the kidnapper is human. As Dean tries to find him, the two brothers learn that some human hunters are looking to do some sadistic hunting of other humans.
Sam and Dean examine a series of murders in Chicago and after running into Meg there, discover that she is the killer behind them. She begins to utilize the services of shadow spirits to keep them at bay, but the two then come to understand that her efforts aren't really about them, but rather about enticing their father to the scene.
Sam and Dean look into the legend of a man named Mordecai, who killed his six daughters during the 1930s and whose spirit is now terrorizing a house.
Sam and Dean investigate the presence of a witch in a Wisconsin town, one who can put children into comas and in effect steal their very essence. The case opens up an emotional wound for Dean, as he harrowingly fought to keep Sam away from the witch as a child.
Sam and Dean must unravel the mystery of an early twentieth century painting which mysteriously has been responsible for the murders of each and every one of its owners.
John makes a shocking appearance to help Sam and Dean solve the murder of John's vampire hunter mentor, Daniel Elkins. When the hunt leads them on the trail of a powerful old gun with the ability to kill all things supernatural, the trio determines to obtain the weapon in hopes of finally vanquishing the demon responsible for the loss of Sam and Dean's mother.
Sam, Dean and John head to Salvation, Iowa, when Sam comes to believe through a vision that one family is going to be the victim of the same demon that took their mother. Though they have the Colt gun in their possession, Meg informs them that she is going to kill off their friends unless she gets it back, but John decides to throw her off the trail by giving her a fake.
Sam and Dean enlist the help of a longtime family friend, Bobby, when they attempt to rescue John from Meg's captivity, using Bobby as bait to help rid Meg of the demon. The brothers then have a final showdown with the now-released demon.