Bracing themselves for the possibility of an apocalyptic war, Sam and Dean realize they have an enormous task of hunting down the hundreds of demons that escaped from the Devil's Gate. With only a year left to live, Dean decides to live life to the fullest and exhibits a carefree attitude that troubles Sam, who is trying to find a loophole in the deal. Bobby tells the brothers about a sighting in Nebraska that turns out to be seven demons that are the actual manifestations of the Seven Deadly Sins.
Dean pressures Sam into visiting Cicero, Indiana, so he can visit an old flame named Lisa, he had a tryst with nine years ago. However, Dean is stunned when he meets not only Lisa again, but also her 8-year old son Ben, who bears a striking resemblance to him. However, Ben soon goes missing and Sam and Dean discover that a Changeling, a demonic parasite, is snatching kids from the small town and assuming their form. Meanwhile, Ruby makes contact with Sam and reveals some startling information about his mom.
Sam and Dean answer a call on their dad's old cell phone, alerting them someone has broken into John's secret storage room in New York. They discover a cursed rabbit's foot has been stolen and call Bobby for help. He advises them to beware of the foot because anyone who touches it will receive an extreme amount of good luck, but once the foot is lost that person will die. Unfortunately, Sam has already handled the foot, which causes an overjoyed Dean to buy lottery tickets, but a female thief steals it from Sam causing his luck to plummet and putting his life in danger.
Sam and Dean investigate a rash of violent deaths in Elizabethville, Ohio, a once-sleepy town that has been turned into a haven for gamblers and drinkers. Dean discovers demons have infiltrated Elizabethville and are using their powers of persuasion to make the townspeople succumb to their basic instincts. Meanwhile, Ruby helps Bobby rebuild the Colt from scratch and stuns him with some news.
Sam and Dean investigate a small town that has been plagued by a number of strange murders that resemble fairy tales, such as Little Red Riding Hood, Snow White and Hansel and Gretel. Meanwhile, Sam summons the Crossroad Demon and threatens to kill her with the newly rebuilt Colt unless she releases Dean from his deal.
Sam and Dean investigate the mysterious demise of drowned victims who were nowhere near the water at the time of their death. The brothers learn each of the victims saw a ghost ship shortly before they died. Upon investigation, they cross paths with Bela, who is being paid handsomely by one of the murder victim's family members to solve the case. Sam and Dean warn her to stay out of their way, but she has other plans.
Sam and Dean capture a female vampire named Lucy who claims to have no knowledge of how she became a vampire. The guys discover Dixon, a male vampire, is giving out human blood to unsuspecting females in bars, offering it up as the "latest drug" and turning them all into vampires. Meanwhile, Gordon escapes from jail and goes after Sam. However, Dixon intercepts Gordon and turns him into a vampire, which makes Gordon more powerful than before and a much bigger threat to Sam.
It's Christmas time and Sam and Dean investigate a series of murders where the victims were pulled up through the chimney. Sam realizes they are dealing with a sort of Anti-Santa, a demon with roots in pagan lore. Dean wants to celebrate Christmas the old fashioned way as this is his last, but Sam refuses, not wanting to accept that Dean won't be around next year. Sam flashes back to a certain Christmas when he waited for his father to come home to give him a special gift.
Sam and Dean travel to Sturbridge, Massachusetts, and discover a coven of witches that has killed two people. Ruby warns the brothers to stay away as the demon controlling these witches is very powerful and will surely kill them. Ignoring her plea, Sam and Dean go in after the coven and confront the head witch, who reveals Ruby's past.
Sam and Dean race to Bobby's side after he lapses into a coma and can't be awakened. While unconscious, Bobby battles his personal demons and the reason he became a hunter is revealed. Sam and Dean discover someone poisoned Bobby with a potion that will kill him if he doesn't wake soon. When the brothers decide to take the potion themselves to enter Bobby's dream in order to save him, they come face to face with their own personal nightmares.
Sam and Dean investigate the disappearance of a man who went missing at a tourist location. While searching the site, Dean is shot and killed by the owner. Sam is devastated but stunned when he wakes up the next morning to find Dean alive and well. As the day unfolds, Sam realizes he is re-living the previous day and tries to prevent Dean's death, but to no avail. Dean dies again and Sam must learn to live life without his brother by his side.
Sam and Dean break into Bela's apartment in order to get the Colt back, but she has tipped off Agent Henricksen about their whereabouts and they are arrested. While Sam and Dean are locked in a cell in Colorado, a demon breaks in and kills some of the sheriff's men and possesses Henricksen. After the guys vanquish the demon, the FBI agent realizes they were telling the truth and prepares to release them, but Ruby shows up to a warn Sam and Dean that the jailhouse is surrounded by a band of demons with a powerful new leader who wants Sam dead.
Sam and Dean take a break from their usual gig to star in a gritty reality show called "Ghostfacers" which chronicles the pursuit of the paranormal. Ed Zeddmore and Harry Spengler have created a radically different and sometimes violent show full of profanity that takes them to the Morton Mansion, an abandoned estate which becomes one of the most haunted places in America one night each year. However, as their team begins to get picked off in grisly manners not fit for television, they realize they are in over their heads.
Dean is stunned after he receives a phone call from his dad who tells him he has a solution to get Dean out of his deal. Sam and Dean fight because Sam is skeptical that it is really John on the other end of the phone and warns Dean not to listen to him but Dean disagrees and sets off on his own path to follow his father's orders.
As time runs out for Dean, Sam convinces him to head to Eerie, Pennsylvania to investigate a possible zombie case. Instead, they discover Doc Benton, a real-life doctor who, in 1816, abandoned his medical practice to follow his obsession with finding the key to eternal life by drugging people and stealing their vital organs. Meanwhile, Bobby finds out where Bela is hiding, and Dean heads out to confront her, leaving Sam behind to deal with the good doctor. Dean and Bela battle it out for the last time, and Dean leaves Bela in a desperate, and possibly fatal, position.
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.