Sam and Dean prepare for Lucifer's arrival only to find themselves on a plane flying overhead. Castiel is destroyed by the Archangel, and the brothers are left to work with Bobby to pick up the pieces and take on angels and demons alike as Zachariah reveals his master plan.
Hunter Rufus Turner calls in Bobby, Sam, and Dean to deal with a demon infestation in his town, but they soon discover the truth is much more horrifying. Meanwhile, Castiel goes to seek the only entity that can defeat Lucifer.
Sam gives up hunting but several visitors in his new life makes his vow difficult to keep. Meanwhile, Castiel seeks out the archangel Raphael to learn the whereabouts of God, and asks Dean to help him.
After Dean refuses Sam's offer to team back up, Zachariah transports Dean five years into the future to witness the Apocalypse after Dean refuses to become a vessel for Michael. Humans transformed into zombies by the Croatoan Virus roam the earth and Dean's future self and a small band of rebels are mankind's last hope against Lucifer himself.
Sam and Dean take on their first post-reunion case when a man is killed in a head-on collision... in a parked car in a garage. The brothers soon realize that the killer is taking on the appearance of famous real-life icons and killing their greatest fans, and a wax museum holds the key to locating the killer.
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.
When Sam and Dean find themselves living their lives on what appear to be TV shows, it makes for a whole new style of reality television and they wonder if the Trickster is to blame. From a sitcom to a soapy hospital drama to a Japanese game show to a crime procedural, each new experience they encounter is more bizarre than the next and they want out. But is the Trickster really the mastermind behind the madness?.
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.
A 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 (now Sam) 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 Baldur 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.
When the Winchesters run out of options, Sam decides that he must open himself to Lucifer and hope that he can maintain control long enough to seal Lucifer away. However, he soon discovers that he is in over his head, and his brother and friends must pay the price.