|“||No, Sam, it doesn't matter. (...) What I've been saying for months.(...) Ever since what?! We lost pretty much everyone we ever cared about? Ever since the Mark made Cass go crazy? Ever since I had to bury him in a Ma'lak Box? Ever since then?! Yeah! You know why? Because the monsters, they're everywhere! Everywhere! What we do, its not even hunting anymore. It's whack-a-mole. We don't even save people. Every friend we've ever had is either dead, or they got wise and they packed it in. (...) We lost, brother. We lost. I'm done.||”|
Using the spell given to them by Michael, the Winchesters and Castiel were able to lock God away. On April 17, 2020, while Sam, Dean, Castiel and Eileen were about to enjoy a movie night, they received a call from Jody that a vampire hunt had gone wrong, leaving Claire dead.
By January 6, 2021, the world had taken a turn for the worst with the Winchesters having recently been unable to save a bunch of victims from werewolves. Dean insisted that there was nothing they could've done as the place had been "crawling with wolves" and they had to wait, but Sam insisted that because they waited, the victims all bled out on the floor. Though Castiel could've healed them, Dean had been forced to lock his best friend away in a Ma'lak Box after the Mark drove Castiel crazy. Dean recognized the reality that the monsters were winning now. At some point after this, Eileen was killed on a hunt, leaving Sam devastated.
On November 3, 2021, Dean found Sam getting ready to go on yet another hunt despite having just gotten back. However, Dean, having given up after losing all of their friends, refused and argued with Sam who he felt had a death wish ever since losing Eileen. Sam asked Dean about his plans to go out swinging like Butch and Sundance, but Dean simply stated that they had lost and he was done. Dean walked away, leaving behind Sam who decided to keep going on his own. Sam later found Dean drinking in the library and insisted that he was raiding the nest with or without him and Dean went along, feeling that he didn't really have a choice. The hunt went wrong and Sam and Dean were turned into vampires themselves.
On December 9, 2022, Sam and Dean, chased by four other hunters, including Jody and Bobby, locked themselves in a motel room and prepared for a last stand. After a brief struggle with one of the hunters, Dean threw him out the window to his death as Sam stabbed the other hunter to death. After seeing Jody shoot Sam with a dead man's blood bullet, an enraged Dean turned on his former friend, disarmed her and flipped Jody onto the bed where Dean ripped out her throat and drank her blood. As Dean killed Jody, Bobby entered and decapitated Sam, causing Dean to turn on him.
This timeline and version of Sam was erased from existence after Sam chose not to trap God based on what he saw.