This demon, Lilith, is trying to break the 66 seals to free Lucifer from Hell. Lucifer... will bring the Apocalypse. So... smoke 'em if you got 'em.
In Supernatural, the Apocalypse is a series of disastrous events leading up to and including the end of the world.
Soon after Dean's resurrection, hunters are attacked by the ghosts of people they could not save. Bobby's research uncovers an obscure translation of the Book of Revelation that lists the ghosts, or the Witnesses, as a sign of the upcoming Apocalypse. Castiel confirms that demons, under Lilith, are attempting to break the 66 Seals and free Lucifer from his prison.
The Winchesters, Bobby, and angels fight to stop other seals from breaking, but they steadily lose ground. There are 600 possible seals, however, only 66 need to be broken and no one knows which ones Lilith plans on breaking. They discover that the first seal was broken by Dean in Hell, when he became a torturer. Alastair explains that the first seal had to be broken before any others to get the desired end result. After Dean's death at Lilith's hands, Sam gets determined to kill Lilith, who he has been told is the only being that can break the final seal, while angels tell Dean that it is he who must prevent the Apocalypse. The brothers conflicting beliefs concerning Sam's relationship to Ruby, his addiction to demon blood, and his psychic powers causes a rift between them.
It was later revealed that the higher ranking angels including Michael, Raphael and Zachariah want the Apocalypse, and hold Dean in the Green Room while Sam seeks out Lilith with Ruby. Castiel frees Dean and sends him after Sam, but Sam kills Lilith, whose death is actually the final seal. Lucifer's cage opens, and the Apocalypse begins.
Immediately, Sam and Dean hear of earthquakes and disease spreading. Zachariah confronts the brothers, and reveals that the real carnage will not start until Lucifer enters his preordained vessel.
Zachariah: Lucifer is powerful in ways that defy description. We need to strike now, hard and fast—before he finds his vessel.
Sam: His vessel? Lucifer needs a meat suit?
Zachariah: He is an angel. Them's the rules. And when he touches down, we're talking Four Horsemen, red oceans, fiery skies—
Zachariah also reveals that Dean alone cannot possibly kill Lucifer, but he tells Dean that he is Michael's vessel, and once occupied, he can defeat Lucifer. Once Lucifer is defeated by Michael, angelkind believes that he will bring paradise to the Earth. Sam learns later, from the Devil himself, that he is Lucifer's true vessel. Neither brother is willing to consent to serve as a vessel, postponing the final battle. Michael remains disembodied, but Lucifer finds a temporary vessel in Nick.
Demons fall in line behind Lucifer, and his plans proceed. He intends to destroy humanity, and essential to his goals are the Four Horsemen of the Apocalypse. War is the first encountered by Sam and Dean. He causes an entire town to kill each other by making them see demons. Famine, a weakened but still intimidating figure, is cared for by demons at Lucifer's direction until he becomes powerful enough to march across the land with authority. Pestilence, again assisted by demons, devises a scheme to spread the Croatoan virus in the form of a vaccine for swine flu. Death, having been imprisoned since the Great Flood, is released by Lucifer and bound to him to force his obedience. With Death under his control, Lucifer orders still greater disruption. The Whore of Babylon also serves as an instrument of destruction and misinformation. Jesse Turner, the Antichrist, was supposed to play an important role during the destruction of Earth, but he turns away from Lucifer's plans.
Sam and Dean follow omens, (including forest fires, biblical storms, and the dead rising) and combat what they find. Other hunters are hostile toward them because it is rumored that they are directly responsible for starting the Apocalypse. They are constantly assaulted by both angels and demons who want to force them to serve as vessels so that the final battle between Michael and Lucifer may take place; all parties involved claiming that it is their destiny. They try and fail to kill Lucifer with the Colt, losing Ellen and Jo in the process. Dean, slowly worn down by the ominous warnings of others and afraid that Sam will give in to Lucifer's temptations, decides to say yes to Michael. However, he manages to step away from his destiny after seeing the faith Sam had in him. Dean kills Zachariah and leaves Michael, who takes Adam Milligan, Sam and Dean's half-brother, as his host.
When they learn from Gabriel that Lucifer can be re-imprisoned using the rings of the Four Horsemen, Sam, Dean, Bobby, Castiel, and Crowley do whatever it takes to acquire the rings. Sam comes up with a plan to say yes to Lucifer, so that the archangel will enter him and he can gain control just long enough to throw himself into the pit, dragging Lucifer along with him. Team Free Will is reluctant to agree, but eventually realize that it's the only way to stop the Apocalypse, after Death confirms that Sam's plan is viable. Sam gives Lucifer his consent, but is unable to control him. They go to Stull Cemetery to meet with Michael and begin the final battle. However, Dean interrupts, and gives Castiel enough time to banish Michael long enough for Dean to make an attempt to reach Sam. After Lucifer kills Castiel and Bobby and turns his attention to Dean, Sam manages to wrestle control back from the archangel and use the Horsemen rings to open the portal. Michael tries to stop him, but he and Adam end up getting imprisoned along with Lucifer and Sam. God revives Castiel as a Seraph, who in turn revives Bobby. With the Apocalypse stopped, Dean decides to quit the hunting life and goes to live a normal life with Lisa and Ben Braeden.
First Angelic Civil War
Following soon after the events of 5.22 Swan Song, a civil war breaks out in Heaven between Raphael and Castiel. Raphael gathered a group of traditionalist angels in order to conquer Heaven and restart the Apocalypse. Castiel, and many other angels, have waged war against him, wanting to prevent the world from ending. The two angels started racing each other to gather a number of Angelic Weapons stolen by Balthazar to rally their forces. Castiel says " Whoever has the weapons wins the war." While Castiel is able to reach Balthazar first, he is reluctant to give him the weapons as he is selling them in exchange for souls. Eventually, after Raphael starts targeting everyone associated with Castiel, Balthazar decides to send him and Virgil on a wild goose chase after the Winchesters into an alternate universe while he locates and provides the weapons to Castiel. With these weapons, Castiel is able to strengthen his forces considerably. According to Bartholomew, Castiel even defeated Raphael and a majority of his loyalists with a small unit of 20 angels. 
In an attempt to defeat Raphael and win the civil war, Castiel has formed an alliance with Crowley to find Purgatory and raid the souls of dead monsters to gather enough power to kill the archangel. However, this catches the attention of Eve, who after learning that they are torturing the Alphas, her children, escapes from Purgatory and attempts to create the perfect beast in order to transform every human into monsters so that all the souls on Earth will go straight to her upon death. Crowley wanted Eve captured alive to study her, however she is killed by Dean with the ashes of a phoenix. However, Castiel manages to locate and capture Eleanor Visyak, a purgatory native, and torture her for information on how to open a portal to Purgatory and steal the souls. After Crowley targets Dean through Lisa and Ben Braeden, Castiel puts his alliance into question. He eventually double-crosses the demon, intending to take all the souls for himself. In retaliation, Crowley makes an alliance with Raphael and they force him to surrender the blood they need for the spell. Unbeknownst to them, Castiel switches it with dog's blood and performs the ritual in secret. When they realize the deceit, Crowley makes his escape while Castiel obliterates Raphael with a snap of his fingers, effectively ending the war. Afterwards, he decides to kill all of Raphael's followers and take command of Heaven, Hell, and Earth. However, the leviathans, which Castiel absorbs along with the souls of Purgatory, start to take control of his vessel and attempt to escape into the world. Castiel works with Bobby and the Winchesters to return the souls to Purgatory. Unfortunately, the leviathans manage to hold on, kill Castiel from the inside, and release themselves into the world. 
After having been released from Purgatory, the leviathans plan to turn humanity into a perfect never-ending food source. To accomplish this, they started building slaughterhouses for humanity in various locations and plant an additive into the food that makes humans pliable and cause weight gain. Vamptonite also kills all other monsters that feed on humans such as vampires, werewolves and ghouls. They also created Additive 3.0, which is intended to be added in non-dairy coffee creamer that breeds out unwanted traits (naturally lean people, short people, hemophiliacs, and those with a high IQ) and kills people who have such traits. The leviathans also planned to build stem cell research facilities to cure diseases (cancer, AIDS, heart disease) so that their food supply will be disease free. Their plan is to live on Earth forever in a luxurious lifestyle while humanity is knocked off the top of the food chain and sent to live and die like cattle.
The Word of God tablet on the Leviathans reveals the only way to kill them:
"Cut off the head, and the body will flounder. Waste not thy time nor your breath upon the Leviathan herd. Point thy blade at the heart of their master, for from him springs all their messages. Leviathan cannot be slain but by a bone of a righteous mortal, as light and good as the Leviathan are hungry and dark, washed in the three bloods of the fallen: a fallen angel, the ruler of fallen humanity, and the father of fallen beasts."
Dean, Sam and Castiel use this to fashion a weapon using the bone of a nun, and the blood of Castiel (a fallen angel), Crowley (ruler of fallen humanity) and the Alpha Vampire (father of fallen beasts). Dean and Castiel use the weapon on Dick Roman, their leader, but get sent to Purgatory in the process. As a result, the remaining leviathan go incognito indefinitely.
When the Mark of Cain was removed from Dean, it released the Darkness (aka Amara), God's sister, from her imprisonment. Amara seeks to lure God out of hiding and eventually kill him after making him watch as the world is destroyed. God (aka Chuck) has decided to let Amara destroy the world, but Metatron convinces him to save humanity. Chuck lends his help to Sam and Dean, but ends up getting mortally wounded, causing a disruption in The Cosmic Balance. When Chuck dies, all of creation will cease to exist, including Amara. Dean manages to convince Amara to put her rage aside and ask herself what she really wants. Chuck and Amara reconcile when she realizes that she wants them to be a family again. She heals Chuck of his wounds and the two leave Earth together to have a family meeting.
Apocalypse World is a version of Earth in which the forces of Heaven and Hell are fighting with humanity caught in the middle. In this world, when offered a deal by the Prince of Hell Azazel to resurrect John Winchester, Mary Campbell refused. As a result, Sam and Dean never existed and thus did not stop the Apocalypse from happening as they did in their world.
Upon arrival in the Winchesters' world, Michael begins to experiment with monsters, enhancing their abilities and making them invulnerable to conventional methods of death. After trial and error, Michael manages to refine the process. He makes deals with dozens of monsters, motivating them to kill as many hunters as possible. Soon, he tries to turn the entire town of Kansas City, Missouri to make his monster army grow in size. Michael's original plan was to bring paradise to the Earth by wiping out the humans, keeping only as many as the monsters need for slave labour and a steady food supply, but after realizing that Chuck is a writer who throws the worlds he creates away, including his own, Michael decides to burn every single world to the ground until he catches up with God and kills him. However, Michael is imprisoned in Dean's mind for a time. When he manages to escape, Michael possesses Rowena and kills the other Apocalypse World hunters before turning his attention to the Winchesters. Jack Kline manages to use Enochian magic to exorcize Michael and kill him at the cost of burning off his soul to save Sam, Dean, and Castiel.
Sam, Dean, Castiel, and Jack discover that Chuck has been manipulating the Winchesters' lives as part of a sick story, even taking advantage of Dean's grief over Mary's death to trick him into killing Jack at the cost of his own life. When they no longer want any part of his story, Chuck kills Jack himself and opens a portal to Hell, releasing the billions of damned souls and unleashing a horde of zombies to kill the Winchesters and end the world.
The term "apocalypse" is Greek in origin, and means "revelation"; the Book of Revelation is the last in the New Testament. It is a vision of the end times that relates specific milestones that correspond to the opening of seals in the book of judgment. The first four seals release the Four Horsemen of the Apocalypse. The fifth concerns martyrs, and after the opening of the sixth seal, disasters begin. When the seventh seal is opened, lightning, earthquakes, hail and fire, the burning of trees, mass extinction, poisoned waters, and monsters plague the earth. The Whore of Babylon appears in verse 17:5, and the imprisonment and escape of Lucifer are in chapter 20.
The bible also speaks of Two Witnesses to the end of times such as Moses and Aaron. They would bring all manner of plagues to the Earth and after finishing their testimony, the Devil will make war on them and conquer them. The people would rejoice at their deaths and refuse to give them proper burials. After three-and-a-half days, they would be resurrected and strike fear into the people before ascending to Heaven.
“And I will give power to my two witnesses, and they will prophesy one thousand two hundred and sixty days, clothed in sackcloth.” These are the two olive trees and the two lampstands standing before the God of the Earth. And if anyone wants to harm them, fire proceeds from their mouth and devours their enemies.”
– The Bible, Revelation 11:3-5
A discussion of the end of days or Judgment Day appears in Judaism, Christianity, and Islam, though interpretations and signs vary.
The Apocalypse in Fandom
- 4.02 Are You There God? It's Me, Dean Winchester
- 4.09 I Know What You Did Last Summer
- 4.16 On the Head of a Pin
- 4.22 Lucifer Rising
- 5.01 Sympathy for the Devil
- 5.18 Point of No Return
- 5.22 Swan Song
- 6.03 The Third Man
- 6.15 The French Mistake
- 9.14 Captives
- 6.19 Mommy Dearest
- 6.21 Let It Bleed
- 6.22 The Man Who Knew Too Much
- 7.01 Meet the New Boss
- 7.02 Hello, Cruel World