Sam, Dean, and Bobby deal with the ramifications of the Gate to Hell opening, meeting the demon incarnations of the Seven Deadly Sins, while Dean is living life to the fullest in the shadow of a deal he made with the Crossroads Demon, and a mysterious blonde woman with a demon-killing knife assists Sam.
A strange death reported in the newspaper prompts Dean and Sam to find Lisa Braeden, a woman Dean had a weekend fling with about 8.75 years ago, only to find she has a son turning 8. While investigating the death in the paper along with several other mysterious recent deaths, Sam and Dean find they are chasing a Changeling, who is replacing children with it's offspring. The mysterious blond woman is back, giving Sam a cryptic message that he should look into his mother's friends.
The Winchesters are called regarding a robbery of their father's storage unit, and track down the robbers to find the item stolen is a cursed rabbit's foot, which provides great luck until lost, and once lost the previous owner dies within a week. Sam picks up the foot and has great fortune, until it is pickpocketted away by the mercenary Bela. Dean must then get it back before Sam's bad luck gets him killed. To complicate the whole situation, Gordon, from his prison home, has convinced two other hunters that Sam is pure evil and must be killed.
The Winchester boys head to Ohio to research several deaths in a small town, where sin has taken a firm foothold on the population; prostitution, adultery, alcohol abuse, murder, and suicide are all prevalent in the once quiet town. Dean has a revealing conversation with a demon possessed woman. The demon Ruby assists Bobby in restoring the Colt to it's demon-killing grandeur.
The 'Three Little Pigs' and 'Hansel and Gretel' come to life and attract Sam and Dean's attention to Maple Springs, NY, where they try to prevent 'Little Red Riding Hood', 'Cinderella', and 'Snow White' from having unhappy endings. Sam also confronts the Crossroad Demon with the newly refurbished Colt.
Strange land-locked drownings are happening and the boys head to the coast to find out why, discovering a Ghost Ship has been witnessed by each of the victims shortly before their deaths. They find that Bela is already involved, running a scam on elderly Gertrude Case, the aunt of the first victim with a crush on Sam.
Gordon Walker is out of prison and out for blood, Sam's blood, and pays Bela to reveal their location. Meanwhile, the Winchesters are hot on the trail of a vampire named Dixon, who in turn has a beef with Gordon.
Sam and Dean follow the trail of an Anti-Claus when victims are apparently pulled up the chimney never to be seen again. After a lead goes nowhere, the Winchesters learn the Anti-Claus in in fact a pair of old pagan gods who have assimilated into society and have found a new way of getting their yearly sacrifices. A flashback to Christmas Eve 1991 reveals how Sam found out for the first time what their father really did and where Dean got his gold amulet.
The Winchesters encounter the mysterious and very much still alive Doc Benton when they look into a series of abductions where the victims report missing body parts after forced surgery. When Bobby manages to locate Bela, Dean heads off to confront her and get the Colt back. Meanwhile Sam stays behind hoping that Doc Benton can make Dean immortal to get him out of the Deal.
Dean's time is up and he has to pay the Devil his due. When Lilith resurfaces in New Harmony, Indiana terrorizing a family to no end Sam, Dean, and Bobby steal Ruby's knife and confront the mother of all demons in a battle to the death.