When the gates to Hell open, seven of the demons take up shop in Lincoln, Nebraska, and start a string of bizarre killings. Two hunters, Tamara and Isaac, help Sam and Dean take care of the demons, but soon find they're being hunted as well. A mysterious blonde woman with a mystic knife also comes to their aid, but it's not clear who she's working for.
Sam and Dean go after demons targeting mothers and their children. While on the hunt, Dean runs into Lisa, a woman from his past, who has a son that reminds Dean of himself at that age. The son, Ben, soon goes missing and Dean and Sam uncover that a Changeling is kidnapping kids from the small town and taking over their form. Meanwhile, Ruby meets up with Sam and reveals startling information about his mother.
Sam and Dean receive a call on their father's cell phone telling them that someone has broken into John's storage room in New York. There, they find that a cursed rabbit's foot has been stolen and call their old friend Bobby for help. Bobby tells them that whoever has touched the foot will have good luck until they lose the foot, which will result in the person dying. Since Sam has touch the foot, Dean buys lottery tickets, but when a thief steals it, Sam's life is in danger.
Sam and Dean investigate a group of unhappy deaths in Elizabethville, Ohio, a town that has quickly become home to many gamblers and drinkers. The execution of each death seems to follow a particular pattern of steps. Dean finds that demons have infiltrated the town and are using persuasive powers to help the townspeople succumb to basic human instinct. Ruby and Bobby rebuild the Colt, and Ruby delivers shocking news.
A young girl trapped in a coma by her wicked stepmother sets off a series of murders based on the fairy tales her father reads her. Meanwhile, Sam tries to get Dean out of his deal.
Bela gets in the way yet again as Sam and Dean are investigating multiple victims who drowned even though they were nowhere near water. Sam and Dean make the creepy discovery that the victims all saw a ghost ship right before dying. They tell Bela to stay away, but she's not so willing to leave, as someone's paying her a lot to solve the same case Sam and Dean are investigating.
Sam and Dean capture Lucy, a female vampire, who has no knowledge of how she became a vampire. The brothers come across Dixon, a male vampire, who gives blood to females he meets in bars, telling them it's the "hottest new drug". Meanwhile, after escaping from prison, Gordon sets out to find Sam, but when Dixon intercepts him and turns him into a vampire, Gordon is now an even bigger threat to Sam.
It's Christmas and Sam and Dean look into the murders of people who were pulled through their chimney. While investigating, Sam learns that they are dealing with an Anti-Santa, a demon that has roots in pagan lore. When Dean wants to have an old-fashioned Christmas, Sam has flashbacks to a Christmas where he waited for his father to come home with one special gift.
The seemingly harmless practices of a group of neighborhood witches goes bad when one of them kills a woman. Ruby offers her assistance... but she has a few secrets of her own.
Dean interrogates a college student after the death of Dr. Greggs. Bobby, Sam and Dean all discover the truth behind the fatal death when they all get locked in a nightmare of their own.
While investigating the disappearance of a missing man, Sam and Dean have to break in to the place where he disappeared, but they get caught, and Dean is shot and killed by the owner. When Sam wakes up the next morning he is shocked, Dean is alive, but as the day continues Sam realizes that they are re-living the previous day so he tries to stop Dean from getting shot, but he fails and Dean dies again... and again... and again, so Sam has to learn how to continue on without his brother.
Sam and Dean break into Bela's apartment to find the Colt, but Agent Henricksen is on the scene and arrests them both on the spot. While Sam and Dean are locked up in a jail in Colorado, a demon breaks in, kills the police, and possesses Henricksen. After the brothers do away with the demon, the FBI release release them, only to learn from Ruby that the jailhouse is surrounded by demons who want Sam dead.
Sam and Dean end up appearing on Ghostfacers, a reality TV show created by ghost hunters Ed Zeddmore and Harry Spengler. They all find themselves at the Morton Mansion where every year someone mysteriously disappears never to be seen again. Now the brothers must protect the Ghostfacers and defeat the ghost.
Sam and Dean search for a Crocotta that uses the phone and computer as a means to communicate with people. Its goal is to get people to commit suicide and take their soul. Dean gets some news from an unlikely source about a demon holding the contract to his soul.
Sam and Dean discover a doctor who, back in 1816, became obsessed with finding the secret of eternal life by taking people's vital organs. Meanwhile, Bobby finds Bela and Dean leaves Sam to confront her.
It's 30 hours before Dean's deal with the crossroads demon is up and Dean, Sam and Bobby are searching for Lilith, who holds the contract. They discover her location and Sam summons Ruby for help despite Dean's protests. Ruby warns them they aren't ready to fight Lilith yet but they steal her knife and depart for New Harmony, Indiana. In a battle to the death, Sam, Dean and Bobby take on Lilith and all her demons in a last ditch effort to save Dean's life.