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.
Sam and Dean are called in to investigate when a plane crashes under mysterious circumstances, leading them to the conclusion that a demon is possessing people and causing them to crash the plane they are on.
Following visionary Sam's recent nightmare about the former Winchester home in Lawrence, Kansas, where the present dwellers, Jenny from Wichita and daughter 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.
Sam and Dean investigate an abandoned sanitarium and discover that when the hospital was open, the patients held a revolt against the cruel and unusual experimental treatments carried out by the head doctor. Now the ghosts roam the halls, driving anyone who spends the night insane. While trying to rescue two lost teenagers, Sam is captured and turns against Dean.