Sam and Dean Winchester were trained by their father to hunt the creatures of the supernatural. Now, their father has mysteriously disappeared while hunting the demon that killed their mother, 22 years ago.
A friend of John's calls Sam and Dean for help about a strange recording on the black box of a crashed plane. They soon realize that the demon which caused the crash is picking off the crash's only seven survivors.
Sam and Dean investigate an age-old urban legend known only as the Hook-Man, the spirit of a 19th century pastor with a twisted sense of morals that is unknowingly being used as an innocent girl's attack dog.
Following visionary Sam's recent nightmare about the former Winchester home in Lawrence, Kansas, where the present dwellers, Jenny from Wichita and mother to two small kids, are suspiciously accident-prone, Dean reluctantly accepts to drive there. Dean and Sam reassure Jenny but follow up on the kids fear of a flaming creature in the closet. They consult Missouri Moseley, their father John's old medium friend, and together with the spirit of Mary Winchester, confront an evil poltergeist, but a second ghost intervenes and someone hides behind Missouri.
While investigating a haunting in an abandoned asylum and rescuing two teenagers who ventured in, Sam and Dean become trapped with the spirits of those who had died in a riot decades ago, one of which was a doctor who causes extreme rage in his victims.
After Dean is fatally injured on a case, Sam thinks he's found a cure in a preacher who performs miracles. However, after they discover that these miracles are not as 'holy' as advertised, the brothers race to stop them before another innocent life is sacrificed.
When Sam's visions start happening while he's awake, he and Dean investigate the unusual murders he foretold only to find them all to be true. And that perhaps he's not the only one with special abilities.When visiting the Millers the boys go as priests.
While looking into a mysterious murder in Illinois, Sam and Dean come across Meg, an old 'friend' of Sam's, who may be far worse than they ever thought possible and who plans to use the brothers as bait to trap their father, John.
Dean gets a second chance to right a wrong from his past when the brothers get a mysterious tip from their father about a case they'd worked years ago, but left unfinished after Sam was nearly killed by the creature.
When two sets of owners of the same painting are brutally murdered, Sam and Dean investigate with the help of an auction house owner's daughter, all while Dean shamelessly tries to pair her with his little brother.
After Daniel Elkins, a vampire hunter and John's mentor, is murdered, Sam and Dean are surprised when John himself shows up to solve the case. John discovers the vampires have taken an antique gun, which has the power to kill all supernatural beings. The Winchester family sets out to retrieve the gun from the vampires so they can use it to kill the demon that took Sam and Dean's mother.
Meg turns to killing John's friends in order to get the Colt. Sam and Dean stakeout the Demon's next target; a family with a six month old baby showing signs of special abilities. John heads off alone to confront Meg.