Sam, a soon-to-be college graduate, has an interview set up to attend one of the most prestigious law schools in the country. His brother Dean, whom he has not seen in several years, unexpectedly shows up in the middle of the night to tell him that their father went missing while on a hunting trip. Leaving his girlfriend behind to find their dad, Sam joins Dean in order to find their father in Jericho, a small town where unmarried men have disappeared without a trace.
Sam and Dean head to Colorado to check out the coordinates that their father left them in his journal. When they arrive, they pose as park rangers to investigate the disappearance of three campers and soon discover that they're up against a Wendigo, a mythical creature from Native American folklore.
While going through the newspaper, Dean comes across a mysterious drowning victim. Upon further research they soon discover more people who have drowned in the same lake, but their bodies were never found. When the boys show up in town they befriend a boy whose father has drowned. The brothers come to believe the lake is haunted by a spirit.
A friend of Dean's calls him up when a plane crashes under mysterious circumstances. Dean and Sam soon discover a flight attendant who was on the plane but they do not realize her full connection to the crash until they are on board another flight with her.
A man dies of a stroke in front of a mirror but Sam and Dean believe something, or someone else (Bloody Mary), may be behind his death. Dean tries to help Sam open up about his girlfriend's death, particularly after Sam lets it slip that there's some information that he hasn't told Dean.
Sam's friend, Zach, is accused of murder. Sam offers to help out by checking up on his sister, Rebecca. Rebecca claims her brother could not have committed the murder because he was with her at the time of the murder. But all the physical evidence points to Zach being at the scene of the crime. Could Zach have been at two places at the same time?.
Sam and Dean help a girl whose date became a victim of the "Hook Man", a famous urban legend that turns out to be real, in a small college town somewhere in Iowa. In order to save her and her father, the local minister, the brothers have to find the ghost's bones so they can destroy them. One tiny problem... they're in an unmarked grave.
A gas & power worker is killed when insects burrow themselves into his brain and consume it. Sam and Dean research the history of the new housing development and find that it has been constructed on former Indian land cursed against the white man. Now, it's up to the brothers to get the people out before they are killed by swarms of bees, locusts, spiders, and beetles.
Sam continues to have haunting dreams and convinces Dean to return home for the first time. There, the brothers have to deal with painful memories, but their feelings are put on hold when the current residents experience the same phenomena that Sam had dreamed about. But before they can stop what's happening now, Sam and Dean have to face their mother's death first.
Sam and Dean travel to an abandoned sanitarium where they find that the patients once revolted against cruel and unusual punishments given to them by the head doctor. The brothers search the area for lost college students, but the spirits make them go insane, and end up turning Sam against Dean.
Sam and Dean part ways when Sam insists on ignoring John's orders and tracking down Jessica's killer. Dean travels to a town that's hiding a dark secret about a scarecrow, and their perpetual prosperity, while Sam meets up with an attractive hitchhiker.
When Dean is accidentally electrocuted fighting a monster, he permanently damages his heart. When he's diagnosed as only having a month, at most, to live, Sam searches for a means to save him and finds Roy Le Grange, a faith healer who may actually be the real deal. After Le Grange heals Dean, the brothers discover that Le Grange is using black magic to bind a "Reaper" to do his bidding... and each healing comes with a terrible price.
Dean and Sam travel to Missouri after Cassie, one of Dean's ex-girlfriends, calls him to investigate two racially motivated murders. They find that each murder involves a black truck that has no driver and leaves no tracks. Meanwhile, Dean has to deal with the feelings that he still has for Cassie.
Sam has a premonition about a man's death that is staged to look like a suicide. Once Sam convinces Dean to investigate the case, they are puzzled when they can't find proof that something supernatural was behind the death. However, they soon realize that the dead man's son, Max, has telekinesis and is using it to kill off his abusive family members.
Sam and Dean head to Minnesota where a young boy witnesses a man vanish into thin air. Shortly after arriving, Sam is targeted by the same abductor, and Dean is left to search for his brother. However, the brothers discover that their kidnappers are humans, using the captives as human prey for their sadistic "hunting expeditions".
While following a lead concerning a mysterious death in Chicago, Sam reunites with Meg. Sam suspects it's more than a coincidence, and Meg soon ambushes Sam and Dean. She explains that it's a trap... for John, using them as bait.
Dean and Sam track down the ghost of Mordechai Murdoch, who haunts an old Texas farmhouse. However, the brothers discover that Mordechai is a tulpa, created by thousands of people believing in it after the fake legend of him was posted on a popular website. Now, Sam and Dean must stop the spirit from killing any more people who enter the house.
When Sam and Dean find articles about a town where children are inexplicably falling into comas, the brothers discover that a Shtriga, a creature that attacks children, is behind the mysterious comas. During the battle, Dean remembers a past battle with the creature that almost resulted in Sam's death.
When a young couple mysteriously die after buying a portrait of a 1910 family, Sam and Dean travel to the scene to investigate the painting. The brothers find that each owner of the painting has ended up dead due to a dangerous spirit bound to the portrait. Can they stop it before it kills again?.
When a vampire hunter and friend of their father's is killed, Sam and Dean are shocked when their father arrives to help them solve the crime. John finds that vampires have stolen a gun that has the capability of killing all evil beings. The brothers, along with their father, set out to get the gun back.
After Sam has a vision of a family being attacked by a demon, similar to the way his mother was attacked, the Winchesters follow demonic signs to Salvation, Iowa, to kill the demon using the Colt. However, Meg calls the family to let them know if they don't give her the gun, she is going to kill their friends.
To save their father, Sam and Dean enlist the help of a family friend, Bobby Singer. When Meg shows up at Bobby's home, the brothers are able to exorcise the demon from her body and get her to tell them where their father is being held. The brothers race off to rescue their father, resulting in a final showdown between the Winchesters and the demon they have spent their lives looking for.