Picking up where the finale left off, Dean and Sam watch as the Devil emerges from Hell. The brothers and Bobby deal with the aftermath of Lucifer rising and the stunning news from Chuck the Prophet that Castiel was blown to bits by the archangels.
Castiel tells Sam and Dean that he is going to search for God, who will be able to defeat Lucifer. Bobby's old hunter friend, Rufus, is panicked about demons attacking his town, and begs Bobby for help. Sam and Dean arrive at the town and realize there is a spell over the townspeople, making them hallucinate that they are demons and causing them to kill one another.
Not sure he trusts himself anymore, Sam decides to give up hunting, but a late-night visitor won't let him off the hook that easily. Dean, intent on stopping the Apocalypse, continues hunting on his own and teams up with Castiel to find the Archangel Raphael, as Castiel believes Raphael knows God's location.
Sam tells Dean he wants to rejoin Dean in the battle of the Apocalypse, but Dean tells Sam that they are better off apart. Later, Dean awakens five years in the future in an abandoned city and is attacked by humans who have been infected with a demonic virus [Croatoan] that turns humans into Zombies. Zachariah appears to Dean and explains that this is the world that exists as a result of Dean saying no to helping the angels fight Lucifer. Dean meets up with Future Dean, who tells him that the virus is the Devil's endgame for destroying mankind.
Sam and Dean decide to start hunting together again and their first case leads them to a small town whose inhabitants are being killed by famous dead icons like Abraham Lincoln and James Dean's car. However, after two teenage girls come forward and claim their friend was kidnapped by Paris Hilton, the brothers aren't sure what they are hunting anymore.
Sam and Dean investigate a series of odd murders that strangely resemble fairytales and urban legends. The brothers track down an 11-year-old boy named Jesse and realize that whatever Jesse believes is coming true. Castiel tells Sam and Dean that Jesse is a serious threat and needs to be eliminated.
Sam and Dean discover a witch is running a high-stakes poker game where the currency is life years vs. money. Bobby sees the game as a chance to get out of the wheelchair and bets 25 years, but loses. As Bobby begins to age rapidly, Dean steps in to save him but also ends up turning into an old man, leaving Sam holding the bag for their survival.
The Trickster throws Sam and Dean into an alternate universe where they are characters in different television series, including a sexy medical show, a Japanese game show, a forensics show and a sitcom. The brothers realize the only way to get out of this world is to play along and become the characters in the shows. However, Castiel appears and warns them this universe is dangerous and they must get out before they become trapped.
Super fan Becky uses Chuck's phone to trick Sam and Dean into attending a Supernatural fan convention, complete with fans dressed up as Sam and Dean. One of the activities is a live action role playing game, but things quickly turn sour after a real ghost appears on the scene.
Sam, Dean and Castiel track down the Colt and head off to find Lucifer to send him back to Hell. It's a hunters' reunion when the crew joins forces with Bobby, Ellen and Jo for what could be their last night on Earth.
Former hunter named Martin, who is currently institutionalized, calls Sam and Dean for help investigating a case in the mental hospital. The brothers get themselves admitted as patients to check out the mysterious monster that is attacking the patients, but their incarceration pushes both to the breaking point as they unleash their inner demons against each other.
Gary, a teenage nerd, conjures up a body-switching spell and changes bodies with Sam. Thrilled by his new handsome and built body, Gary investigates a case with Dean and takes advantage of his good looks and age by hitting on women and getting drunk. Meanwhile, Sam is stuck in Gary's teenage body, dealing with intrusive parents and high school.
The angels send Anna back in time to kill John and Mary Winchester before they can conceive Sam knowing that if Sam was never born then Lucifer won't be able to use him as his vessel. Castiel sends Sam and Dean back to 1978 so they can stop Anna, and the two brothers are reunited with their parents. Mary recognizes Dean as a hunter since he visited her in the past once before but tries to keep the truth from John.
Castiel helps Sam and Dean hunt down Cupid on Valentine's Day after townspeople start to kill each other for love. However, after Cupid tells them he's innocent, they discover Famine, one of the Four Horsemen of the Apocalypse, has arrived in town.
Sam and Dean investigate Bobby's home town where the dead are rising from the grave but instead of attacking humans, they are happily reuniting with their families. The brothers turn to Bobby for help but he tells them not to worry about it and to leave town. Suspicious, Dean investigates and comes face to face with Bobby's dead wife who has no memory of what happened to her. Once the zombies start turning evil, the boys tell Bobby he has to kill his wife but he refuses.
Ambushed by angry hunters, Sam and Dean are shot and killed and sent to Heaven. Castiel warns Dean that Zachariah is looking for them in Heaven so they need to lay low while searching for an angel named Joshua who can help them since he talks directly to God. While searching for Joshua, the brothers run into some old friends and family members.
Sam and Dean are outnumbered by demons, but are saved at the last minute by Rob and his townspeople, who are aware of the Apocalypse, and have been training to fight and kill demons. The small town is very religious and Sam and Dean meet Pastor Gideon, who introduces them to his daughter Leah, whom he claims is a prophet. Leah tells the townspeople they must obey her orders if they want a spot in Heaven but when she starts turning the townspeople against each other in the name of the Lord, the brothers realize they must kill her.
Dean begins to think the only way to stop Lucifer is to say yes to Michael, but the angels decide they don't need him anymore. Dean, Sam and Castiel are horrified at the angels' new game plan and take on Zachariah to prevent an all out war on Earth. Meanwhile, a familiar face returns.
Sam and Dean are kidnapped by a group of gods, including Kali, Ganesh and Bladur and held hostage in a small hotel. The gods want to use Sam and Dean as bargaining chips to stop the Apocalypse, but Gabriel shows up and warns them that if Lucifer finds them he will kill them all. Unfortunately, one of the gods turns on the rest and Lucifer appears.
The demon Crowley tells Sam and Dean he can help them find the remaining Horsemen rings so they can trap Lucifer. The brothers are doubtful until Crowley leads them to Brady, the Handler for Pestilence and Death. However, Brady refuses to give up their locations and sets Pestilence after the Winchesters.
Crowley tells Bobby he will give him the location of Death, the fourth horseman, in exchange for his soul. Knowing Sam and Dean need that fourth ring to stop the Apocalypse, Bobby reluctantly agrees. Sam and Dean confront Pestilence, but he unleashes a deadly virus upon them, so Castiel must intervene on their behalf. Dean has a meeting with Death to discuss Lucifer, and an unholy alliance is formed at a very high price for Dean.
The entire season has been leading up to this showdown between good and evil. With the Apocalypse looming, Sam and Dean realize they are out of options and make heart-breaking decisions that will change their lives forever. A beloved character is killed.