Dean is frantic after Sam collapses and the doctor tells Dean his brother won't make it. Desperate, Dean sends out an all points bulletin via prayer to every angel in the area, asking them to help his brother. In exchange, Dean will owe that angel a favor. Numerous angry angels race to find and kill Dean, but one, Ezekiel, gets to him first. Meanwhile, Sam fights for his life and must face some familiar demons to do so. Castiel struggles to survive without powers.
Dean shocks Sam by popping open the trunk of the Impala and showing him that he has kidnapped Crowley. Kevin freaks out when he sees the King of Hell, but Sam and Dean convince him that they need Crowley to find the demons on Earth. Meanwhile, Abaddon re-emerges and plans to take over Hell.
Ezekiel tells Dean a group of angels is hunting Castiel. Dean and Sam race to find their friend before the angels do. Meanwhile, a homeless Castiel is trying to make his way through the city and comes across some unexpected surprises.
Sam and Dean discover that the table in the Men of Letters house, has an ancient computer attached to it. They figure if they can get the computer on, they can track the angels. Who better to call for help than the best IT girl there is, Charlie ? While moving the massive computer, they dislodge a hidden hexbag that unleashes a magical green-webbed wall. Sam and Dean break through it and discover the one and only Dorothy from Oz. She had trapped herself and the wicked witch in the web years ago to stop the witch from finding the key that would open the gate that connected their world with Oz. With the wall broken, a massive and magical fight ensues that threatens to destroy the Men of Letters house.
While investigating two bizarre murders, Sam and Dean realize there is an eyewitness to both gruesome deaths - a German Sheppard. Anxious to find out if they are dealing with a witch, a skinwalker or other supernatural monster, the guys look up a spell that could let Dean "communicate" with the dog. Unfortunately, the spell comes with side effects that no one saw coming.
Castiel gets a job at a Gas-N-Sip and actually starts to enjoy life as a human. A headline in the local newspaper about some disappearances in the area catches his eye, so he calls Dean to help him investigate the case. Dean knows he needs to keep Sam/Ezekiel away from Castiel, so he tells Sam that he and Kevin need to stay and work with Crowley to decipher the tablet. Crowley agrees to help Sam and Kevin but in return he wants one phone call to hell.
Dean gets a call from an old friend named Sonny asking for help with a ghost. Sonny runs a home for delinquent boys, and Dean was sent there for stealing food when he was younger. Sam is stunned he never knew this about his brother and asks for more information, but Dean dodges his questions. Another murder occurs while Sam and Dean are at the house, so they scramble to find the culprit before anyone else dies. Meanwhile, Dean looks up an old girlfriend and recalls his time at the house.
Sheriff Mills calls Sam and Dean for help investigating multiple murders in her small town. Discovering all four victims belonged to the same church chastity group, Sam and Dean decide to infiltrate by joining the group themselves. When Dean disappears, Sam and Sheriff Mills realize whatever they are hunting has taken Dean too and team up to rescue him.
After a massive angel slaughter occurs, Sam and Dean arrive at the scene to investigate and are surprised to run into Castiel. While investigating, Castiel is captured and tortured. Meanwhile, Dean questions Ezekiel's demands and wonders if it might be time to tell Sam the truth.
Dean is devastated after Kevin's death and vows to find the angel that killed him, not only to free Sam, but to seek revenge. Castiel arrives at the bunker and suggests they try to separate Sam's brain from the angel's so they can talk to Sam and have him expel Gadreel. However, there's one small problem: the only person who knows how to do that is Crowley.
Looking to reclaim his place as King of Hell, Crowley asks Dean for help finding "The First Blade," the only blade that can kill Abbadon. Knowing he owes Crowley a favor for helping Sam, and also wanting Abaddon dead himself, Dean reluctantly agrees and the two set off on a road trip. However, Dean and Crowley are completely unprepared when they find out who has the blade - Cain, the first son. Meanwhile, Sam is back at the bunker with Castiel who notices there is some leftover grace inside Sam. If they can extract it, they can use the grace to track Gadreel. The only problem is the procedure may do permanent damage to Sam.
After finding out that Garth is in the hospital, Sam and Dean go to check on him. Still carrying the guilt over Kevin, Dean lays into Garth about disappearing and demands to know where he's been. Garth makes an excuse and then hightails it away from the guys. Confused as to why Garth would run from them, Sam and Dean do some investigating and are stunned by what they find.
Sam and Dean investigate recent murders where the victims were hundreds of pounds lighter after their deaths. Suspecting witches, the two go undercover at a fancy day spa that all of the victims had attended for weight loss. While Sam is hired as a fitness instructor, Dean takes kitchen duty. After Dean swipes some tainted food and passes out, the guys realize someone is drugging the guests and literally sucking all of the fat out of them until they die.
Sam and Dean are stunned to discover the Men of Letters' bunker is haunted. Their investigation leads them to a storage facility where the demons have been keeping a prize possession. Meanwhile, Castiel is captured by Bartholomew.
Teenage girl is killed and the final selfie she took before the attack shows a ghostly figure in the background. Looking for something to keep them busy, Dean and Sam head to Washington to find the ghost. While the two interview the girl's mother, Betty, they are surprised when she starts talking about cold spots and fritzing. When they ask her about bringing up paranormal signs, Betty replies that the "supernaturalists" who called earlier brought it up. Enter Harry and Ed, the famous supernaturalists.
Dean is frustrated when he can't reach Crowley, who has promised to find The First Blade. When Crowley finally calls Sam and Dean, he tells them he fell off the wagon and has been injecting human blood and needs their help. To make matters worse, he had a demon helping him find blood, but she sold him out and told Abaddon that he and the Winchesters were searching for The First Blade. The brothers need to find the blade before Abaddon does, so they enlist the help of a former member of the Men of Letters.
Dean struggles with the after effects of the Mark of Cain. Meanwhile, Sam hears about a case where straight-laced people are turning into violent murderers. Sam suspects possession and suggests to Dean that they investigate, but Dean tells him to go without him. While interviewing the local townsfolk, Sam meets an elderly woman named Julia, who tells him the Men of Letters came to town in 1958. Josie tells Sam the story of a young man named Henry Winchester and his female companion, Josie Sands. While Sam is away, Crowley tests Dean.
Metatron attempts to get Castiel to join forces with him. Still furious with Metatron, Castiel refuses, which sets a surprising plan in motion. Meanwhile, Sam and Dean capture Gadreel.
Sheriff Mills calls Sam and Dean after she kills a vampire who attacked a prisoner named Annie. They discover Annie was kidnapped by a family of vampires who use her as bait to lure in humans they can then feed on. Sheriff Mills tries to rescue Annie from her captors, but finds out the hard way that family always comes first.
Sam and Dean investigate a case in Chicago, where they discover that various mafia-esque monster families are, unknown to humans, running the underbelly of Chicago. One is a family of shapeshifters run by Margo Lassiter, whose leadership is thrown into question when her brother David returns home. The other reigning family in town is made up of werewolves, lead by Julian Duval. While in Chicago, Sam and Dean meet Ennis, a man with a personal vendetta against the monsters. The Winchesters warn Ennis about heading into the hunter lifestyle, but Ennis refuses to listen and starts down a dangerous path.
Castiel captures one of Metatron's angels and asks Sam and Dean for help with the interrogation. Dean eagerly accepts, which doesn't go unnoticed by Sam. Meanwhile, Abaddon demands Crowley help her kill Sam and Dean. When he refuses, she reveals her shocking bargaining chip. Also, Castiel sets a meeting with Gadreel.
After a massive attack on the angels, Castiel calls Sam and Dean for help. As they leave, Dean's eagerness to bring the First Blade doesn't go unnoticed by Sam who is worried about the cost to his brother whenever he uses the Blade. Meanwhile, Castiel is shocked when he learns the angel that caused the attack was one of his followers and did it in his name. Dean discovers there is a conspiracy amongst Castiel's angel followers and at the heart of it is Tessa, the Reaper.
Dean feels the effects of the First Blade, and Metatron makes his move against humanity. Meanwhile, Sam, Dean and Castiel face shocking consequences when taking the fight to Metatron.