Following the release of Lucifer, Pestilence began working on a plot to spread the Croatoan Virus across the country. To this end, he began spreading a mild case of swine flu to drive people into a panic for a vaccine and set his demon minion Brady up as the VP of Distribution at Niveus Pharmaceuticals to make the so-called "vaccine" which would actually be a way to spread the Croatoan Virus simultaneously.
After capturing Brady, Sam and Dean located Pestilence and defeated him, but not before he warned them that "it doesn't matter. It's too late." With the help of Crowley, they figured out Pestilence's plan and decided to destroy the distribution warehouse to prevent it. In an act of kindness, Crowley used his deal with Bobby to restore his ability to walk which allowed him to join the attack on Niveus along with Sam and Castiel while Dean and Crowley went to confront Death in Chicago.
Reaching the Niveus distribution warehouse, they plan to plant C-4 to blow the place up and pull the fire alarm to get the people out. However, Castiel notices one of the distribution trucks leaving early so they change their plan. As the truck pulls up to the security gate, Castiel knocks the driver out with the butt of his shotgun and opens the gate for the others. However, the two demons in charge notice the truck horn and lock up the warehouse, infecting several people with the Croatoan Virus to help them stop the Winchesters.
As the zombies start to attack the employees, Sam shoots out the lock on a side door and lets out the people trapped on the other side. Entering the warehouse, he and Bobby spot several zombies attacking an employee and quickly kill them. However, they quickly realize that there are more people trapped inside the warehouse and Sam takes off to rescue them, leaving the demon-killing knife with Bobby who is displeased with his actions. While Bobby holds off the other zombies, Sam finds and rescues as many people as he can, killing all the zombies he finds along with way. Along with the zombies, both demons attack Bobby, but he quickly kills them with the knife. Eventually, Sam rescues all the remaining people in the warehouse and all the zombies are apparently killed, but he is unexpectedly attacked by a surviving zombie. Bobby tries to shoot it as Sam desperately holds the zombie off, but is out of ammo. Before Sam can get hurt, Castiel shoots the zombie with his shotgun, killing it.
With all of the zombies and demons dead, Sam, Bobby and Castiel blow up the warehouse and all the Croatoan Virus, stopping Pestilence's plan.
With the virus destroyed, Sam, Bobby and Castiel return to Bobby's house where Dean has gotten Death's ring, the last thing they need to seal Lucifer back in his Cage in Hell. Bobby and Dean discuss Sam's plan to say "Yes" to Lucifer in order to take back control and jump into the pit and seeing Sam in action at Niveus makes Bobby see that Sam will succeed or die trying. He is able to get Dean to back Sam as well and they proceed with the plan not long later.
- Before the raid, Castiel complains about having use a shotgun and not his powers, wondering what the point of such a weapon is. Bobby tells him to just point and shoot and yells at him for complaining about his lack of powers as he didn't know his legs were working at the time. During the attack, Castiel uses the shotgun he complained about to save Sam's life and comments that shotguns are actually pretty useful.
- This is the first time Castiel has been in a fight where he doesn't use his powers or angelic nature in some way, such as when he used the last of his angelic strength to defeat Pestilence. While Castiel does not play a major part in the raid, he proves himself capable even without his powers, using his shotgun to knock out a truck driver and kill a zombie despite never having used such a weapon before.