Content Warning: The following article includes discussions of death and sacrifices.
There are few, if any, where the constant threat of death for every single character is as salient as on Supernatural. Everybody dies, usually multiple times. With such a passionate fandom, there is a slew of characters throughout the fifteen seasons of the show fans get invested in just to have them die off heartbreakingly.
A lot of the time, these deaths will have some genuine narrative purpose, and that will often have something to do with Sam and Dean. Whether it is a deliberate sacrifice of their life or simply dying due to the two brothers' actions or some other variant of the storyline, many characters are killed over the course of the show's decade and a half for the sake of the two Winchesters.
Each Other
The most obvious place to start with characters who have died for Sam and Dean is with Sam and Dean themselves, who have died numerous times throughout the show, starting all the way back in season two.
In terms of actually dying for one another rather than just being killed, that is rarer but still happened. Dean sold his soul to a crossroads demon to bring Sam back to life, eventually dying and going to hell because of it. He also technically dies temporarily to save Sam's soul from hell. As for Sam, his taking over Lucifer in his mind and jumping into the pit was more of a saving the world situation rather than just Dean, but it was memories of Dean and protecting his brother were key in his decision.
Castiel
Like the other two core members of Team Free Will, Castiel dies numerous times over Supernatural, albeit to a much lesser extent than the two brothers, only having six deaths in the series.
His iconic "Hey, Ass-butt!" Molotov leading to death by Lucifer to try and help Sam defeat Lucifer does not really count as dying for Sam and Dean, but he still does it for the brothers. The true sacrifice, though, comes in the third to last episode of the show where he professes his love for Dean and professes his happiness, instigating his death as per his deal with the cosmic entity within the Empty, killing both him and Billie, allowing Dean to live on.
John Winchester
John Winchester, the controversial and divisive parent to Sam and Dean, was the first individual to truly sacrifice themselves for one of the brothers in the show, having a shocking death right at the start of season two of the show.
With Dean on the verge of never returning from death, John strikes a deal with Azazel, saving Dean and killing himself instantly to save his boy, confident in the knowledge he and Sam can get the job done together and take out Azazel.
Pamela Barnes
Moving away from Team Free Will and the Winchester's, Pamela Barnes was a popular side character introduced in season four of the show to help solve the mystery of who gripped Dean tight and raised him from perdition.
Pamela was initially only cost her eyesight when trying to help Sam and Dean, which would have been bad enough but not as bad as death. Of course, as mentioned earlier, everyone dies in Supernatural, and eventually, Pamela did die. While watching over Sam and Dean's bodies as she helps them astral-project, a demon comes and fatally stabs Pamela, who, thankfully, ends up in heaven.
Benny Lafitte
Benny was such a fascinating and out-of-left-field character in season eight of Supernatural when Dean returned to Earth from Purgatory, and he ended up not only staying surprisingly on the good side of things but becoming one of the best friends Dean ever had.
When the vampire returned to Earth, though, he struggled; in no small part to Dean's almost abandonment of his friend. When Dean presents Benny with the opportunity to return to Purgatory to save Sam and Bobby's soul, he takes it, and instead of coming home like he says he will, he sacrifices himself to allow Sam and Bobby's soul to escape.
Gabriel
First appearing in season two as the Trickster, Gabriel survived all the way through to season thirteen, although he made everyone think he was dead for a lot of that time. When he did eventually die, though, it was a heartbreaking death.
Gabriel has an arguably underrated arc in Supernatural, eventually ending his long streak of running away from conflict, which comes to a head in the alternate Earth when he stops running and confronts alternate Michael, dying at his hand so that Sam and Dean could return to their world. He died not only to save Sam, Dean, and the heroes, but also because he felt he had to atone for his past history of running away.
Charlie Bradbury
If there is any death on here that was completely unnecessary, both in-universe and out of it, it is Charlie Bradbury, whose death was not only brutal and heartbreaking but controversial and divisive.
Her dying at all was partially Sam and Dean's fault because they involved her in hunting in the first place. However, she died to help them in season ten, refusing to give up anything to Eldon Frankenstein, and sending her descriptions of Nadia's codex to Sam via email before destroying everything. The consequences of these actions was her death.
Ellen & Jo Harvelle
Mother and daughter Harvelle had one of the most painful deaths of the Kripke-era of Supernatural. They were another pair of characters who sacrificed themselves in a situation that then allowed Dean and Sam to escape death.
Of course, unlike most other sacrifices, there was no chance of escape for one of the two Harvelles, with Jo severely injured by the Hellhounds surrounding the area. Ellen's choice to stay with her daughter was beautiful and heartbreaking for everyone involved. The two blew up the building they were in along, dying with the Hellhounds as Sam and Dean escape, with their deaths having a large effect on Dean and Sam, who loved the pair.
Rowena MacLeod
Rowena MacLeod may be a bit of an unfair entry. She did sacrifice herself, and she did save Sam and Dean in doing so, but her sacrifice was one that saved the whole world.
After Chuck released all the souls of Hell, the villain turned anti-hero turned straight up beloved member of the family used a spell from the Book of the Dammed that required her sacrifice and saw her absorb all the souls of Hell before jumping in the pit akin to Sam in "Swan Song."
Crowley
Like-mother-like-son in regards to their final goodbyes, with a tear-inducing "Bye boys," Crowley also sacrificed himself, dying with finality to save Sam and Dean, as his mother would do a few seasons later.
Unlike most characters, Crowley never really dies and comes back to life. He simply dies long into his reign of brilliance on the show. In order to complete the Rift Sealing Ritual, Crowley destroys himself, thus trapping Lucifer in an alternate reality and allowing Sam and Dean to escape unharmed.