In order to defeat the Knight of Hell Abaddon, hunter Dean Winchester took on the biblical Mark of Cain. Due to the corrupting effects of the Mark, his brother Sam began searching for a cure, culminating in him finding the Book of the Damned with the help of Charlie Bradbury. Despite the dangers, Sam sought out a cure from the Book of the Damned with the help of the witch Rowena, unaware that removing the Mark of Cain would release the Darkness. Due to this, when Rowena removed the Mark of Cain, the Darkness was released upon the world once more.
Following her release, the Darkness infected the nearby town of Superior, Nebraska with an infection that started turning people into Rabids.The first people infected were a road crew just outside of town. some of which attacked and killed a family making their way through. Deputy Jenna Nickerson responded to a 911 call on the situation and killed all of the Rabids, but was injured in the process on a piece of rebar. Other members of the road crew made their way into town, killing and infecting people along the way. A truckload attacked the local hospital and killed or infected everyone inside, trapping Mike Schneider and his newborn daughter Amara inside a closet. During the attack, one of the Rabids bled on Mike, infecting him with the Rabid infection as well.
Shortly after Jenna killed the Rabids, hunters Sam and Dean Winchester arrive to find the scene. As they try to determine what happened, a final Rabid approaches them and they try to warn him off. Jenna kills the last Rabid from behind with a shotgun and after making sure the Winchesters are uninfected, explains what happened. Checking on one of the dead Rabids, Sam finds his infected veins and realizes the Rabids aren't human. Noticing Jenna's wound, the Winchesters decide to take her to the nearest hospital for treatment.
Reaching the hospital, the Winchesters find the aftermath of the attack and speculate about how the Darkness' smoke somehow infected the people after the Darkness was released. As Dean treats Jenna's injuries, Sam searches the hospital and finds Mike and Amara cornered in the closet by one of the road crew. Before Sam can shoot the Rabid, he burns out and dies. Sam is able to get Mike to trust him and Mike explains the attack by the infected road crew. While Mike talks, Sam notices the fact that he too is infected and asks if the Rabids cut or bled on him. Mike confirms it and the Winchesters explain that it appears that the infection is transmittable. Though Jenna has a hard time believing it, Mike confirms that he can feel it inside him. As Mike's infection worsens, the group discusses what to do with him as he will eventually become a Rabid. Mike eventually offers a deal: in exchange for Jenna looking after his daughter, he will go off somewhere to die alone as they get Amara to safety. Jenna and Dean both promise and Mike leaves as a truck full of Rabids arrives.
As Dean loads up on weapons to fight the Rabids, Sam and Jenna argue with him about going after the Rabids "guns blazing" when the Rabids will eventually die on their own. Dean tells Sam that there's no knowing how that will take, especially with the Rabids spreading their infection and its their fault they are in this mess as they released the Darkness. Dean insists that if they don't leave, the baby will die. Castiel then calls to check on them and they inform Castiel of the Darkness' release. Castiel tells them that they might not see him for a while and hangs up without being able to give them any more information on the Darkness.
Realizing that Castiel is likely in trouble, Dean becomes even more determined to shoot his way out to get Jenna and Amara to safety and to then find and save Castiel. However, Sam feels that they have a duty to try to save all of the Rabids as well by finding a cure for them, insisting that their job is to save everyone, not just each other and the baby. Dean reluctantly agrees to allow Sam to stay and try to find a cure while he gets Jenna and Amara to safety.
As three Rabids break into the hospital, Sam draws their attention and leads them on a chase as Dean and Jenna make a run for it. Near the exit, the two encounter Mike, now a Rabid who calls out for his daughter. As Dean and Jenna threaten him at gunpoint, Mike retains enough control of himself to tell them that the baby's name is Amara and lets them past. As they leave, Mike's infection consumes him and he dies. Dean, Jenna and Amara are then able to safely escape the hospital and Superior.
As Dean, Jenna and Amara escape, Sam locks himself in a supply closet where he is attacked by a Rabid nurse. Sam slits the Rabid's throat with a scalpel, but his face is splashed with her blood as she dies, giving Sam the Rabid infection. The three Rabids chasing Sam break into the room and pin him against the wall, but detect his infection and leave him alone. A little while later, Dean calls Sam to tell him that they have safely gotten out of Superior and that the Rabid infection seems to be confined to the town. Sam simply tells Dean that he will find a cure before checking himself out in the mirror, finding the black veins of a Rabid infection on his chest.
By the next morning, several Rabids have burned out and Sam, his infection having progressed to be visible on his neck, assembles a makeshift cattle prod out of tools from a hardware store. Sam then uses a video on his phone to lure in a Rabid named George and tasers him unconscious after confirming that George can still talk. Sam then takes George to the hospital and chains him up and attempts to question George for information. George eventually agrees to tell Sam what he wants to know in exchange for Sam's pudding. As George eats, he tells Sam he was infected that morning, surprising Sam since his infection is much further along than Sam's who was infected the night before. George tells Sam that there's no pattern to the infection, that some people get it fast, others get it slow but they all eventually turn psycho and then die. Sam insists that he will find them a cure, but George believes it to be hopeless and tells Sam he should kill George and then himself.
That night, Sam continues his research into a cure by searching for information on hoodoo and infectious diseases online. George has also succumbed to his infection and died by the time that Dean calls to tell Sam of something strange going on with Jenna and Amara that has caused him to turn around. Sam tells Dean to focus on helping Jenna and doesn't tell Dean that he too is infected.
Awhile later, Sam hears someone singing O Death and follows the song to find the Reaper Billie crouched over one of the Rabid victims. Billie tells Sam that with Death gone the only rule now is that "everything that lives, dies" and when he and Dean die, she will cast them into the Empty so that they can't be resurrected. Sam's infection has progressed close to his face at this point and Billie tells him that she can sense that he will die soon as he's "unclean in the biblical sense." She then departs the hospital.
As Sam makes his way back to the room he's working on the cure in, he spots his reflection in a computer monitor and sees just how far the Rabid infection has spread up his neck. Desperate, Sam goes to the hospital chapel and prays to God for a sign of hope. Nothing happens at first, but as Sam leaves the chapel, he is hit with a vision of himself being tortured in Lucifer's Cage, apparently from God himself. Sam demands to know what the vision he received means as he doesn't understand it, but gets no answer.
Not long later, Sam's infection spreads rapidly until it reaches his hairline. Sam starts to succumb to the infection and as he does, he flashes back on Billie telling him that he's "unclean in the biblical sense." Inspired, Sam tries a web search for "bible purification" and finds a link to Bible passages talking about fire and holy oil. Desperate, Sam pours some holy oil in a metal tray, dunks in a small sponge and lights it on fire. Using a pair of scissors, Sam holds the sponge emitting holy fire near his neck and his Rabid infection burns away, curing Sam.
With an effective cure, Sam devises a trap to cure more Rabids. Sam sets up a circle of holy oil in the hospital chapel and in the middle of it, sets a stereo that he blasts loud music from. The music draws in three Rabids who find Sam standing on the other side of the circle. After the Rabids enter the holy oil circle on their way to him, Sam ignites the holy oil. The proximity to the holy fire burns away the infection in the three Rabids, curing them.
Following his successful cure of the three Rabids, Sam enlists their help and together they cure the Rabids in Superior who are still alive, saving everyone in the town that can still be saved.
After reuniting with Dean, Sam learns that the baby Amara was actually the Darkness' new vessel and had escaped Dean's grasp. Returning to the Men of Letters bunker, they find Castiel who had escaped the angels who were torturing him and is suffering from Rowena's spell.
- According to Jenna Nickerson's grandmother, the news reported the events in Superior to be a big storm. Presumably this refers to the release of the Darkness and it hitting the town. Mike Schneider also called it a tornado after first being rescued.
- Sam locating a cure for the Rabids is the first time a cure for a monster type is demonstrated aside from vampires.
- This conflict takes place at the same time as the Fifth Capture of Castiel.