The sixth season begins with Sam being released from hell and trying to convince Dean to rejoin him in fighting evil. To help persuade him, Sam introduces Dean to a new family led by their grandfather Samuel (Mitch Pileggi).
Sam investigates when babies are kidnapped and their parents are murdered. When he finds a baby who is left behind, he contacts Dean to help with the case. Soon, the brothers encounter a shape-shifter who wants to take the child.
Sam and Dean investigate when several police officers seem to have been killed by the biblical plagues of Egypt. Castiel joins in the probe and reveals there is chaos in heaven and that some of its weapons were stolen.
Sam and Dean investigate a series of suicides in which the victims were told brutal truths that drove them to violence. Their probe reveals the Goddess of Truth, Veritas, is responsible and that her next target is Dean.
Dean and Sam investigate what appears to be a werewolf killing, but their probe reveals a skinwalker posing as a family dog is responsible. When the skinwalker takes human form, he warns the brothers that an alpha skinwalker is planning a mass murder.
Dean is abducted from a crop circle while investigating a UFO sighting. He quickly discovers he isn't dealing with aliens but rather with fairies. Sam searches for him and stumbles upon a world occupied by elves, gnomes and a leprechaun.
Virgins mysteriously disappear, and Dean and Bobby learn that dragons are responsible for the kidnappings. Dean seeks out a weapon to slay the beasts, but he must prove himself worthy before he can claim it. Meanwhile, Death tries to restore Sam's soul.
Sam and Dean are transported to an alternate universe, where they are actors on a TV show called "Supernatural" and are named Jared Padalecki and Jensen Ackles, and they must avoid an angelic hit man who is pursuing them.
Balthazar prevents the Titanic from sinking, but Fate intervenes and starts killing off everyone who would have died on the ill-fated ship. Meanwhile, Castiel tells Sam and Dean that Fate is upset with them and they must kill her if they are to survive.