Dean openly fears and respects Death, due to his immense power. Death, on the other hand, claims to find Dean extremely insignificant, but does take time to converse with him and even help him on occasion. Given how Death helps Dean when he doesn't have to and seems to be more tolerant of Dean's attitude than other humans, he may actually like Dean to some extent as he only ever threatens him, even when he steps out of line, but never actually harms Dean. However, to protect Sam, Dean ultimately kills Death.
Death came to physical form in Abandon All Hope..., but Dean had been whisked away by Castiel moments before. Since his ascension, Dean has encountered Death, and has had numerous interactions with him. Dean himself has died and come back to life many times, avoiding Death.
|“||You have an inflated sense of your importance. To a thing like me, a thing like you, well... Think about how you'd feel if a bacterium sat at your table and started to get snarky. This is one little planet, one tiny solar system, in a galaxy that's barely out of its diapers. I'm old, Dean, very old, so I invite you to contemplate how insignificant I find you.||”|
Dean and Death first meet in Two Minutes to Midnight, as Dean heads out with Crowley to retrieve Death's ring in order to open Lucifer's Cage. Dean eventually finds Death in a pizza parlor in Chicago where a hurricane is coming in. Dean fully intends to attack Death and kill him using Death's Scythe. Death, knowing Dean was coming, causes the blade to heat up and Dean to drop it, before revealing he has the weapon back while inviting him to sit at his table.
Once seated, Death tells Dean to eat, but Dean is hesitant. Dean asks if Death plans to kill him, and Death replies by coldly telling Dean how insignificant he really is, then asks how Dean would feel about a bacteria sitting at the same table as him and being snarky. Death also talks about his comparison to the Universe, how he knows and is of an age similar to God and how he'll reap God at the end of time. Dean was very shocked to hear that and views the encounter above his pay grade, to which Death agrees. He then asks Death why he is still alive, and Death answers that he wants to be free from Lucifer. Lucifer was aware that Death didn't want to work for him, so he bound Death and forbid him from contacting Dean, so he had to wait for Dean to find him. Death offers Dean his ring on a condition: to let Sam to go through with his plan, let Lucifer take possession, regain control, and jump into Hell. Dean is hesitant, but agrees though Death reminds Dean that he can't cheat death and shouldn't think about going back on his word and then give him instructions on how to use the rings to open the cage.
Dean considers betraying Death, but lets Sam go through with it since it's the only way.
|“||This is hard for you, Dean. You throw away your life because you've come to assume that it'll bounce right back into your lap. The human soul is not a rubber ball. It's vulnerable, impermanent, but stronger than you know... and more valuable than you can imagine.||”|
in Appointment in Samarra
Dean attempts to bargain with Death's ring however, Death implies that he already knows where it is, and can get it at anytime. Dean begins to give Death background on the situation, and Death irritatedly tells Dean to stop playing games and get to the point. Dean asks Death to raise Sam's soul hell. Dean also tries to get his brother Adam from hell, but Death tells Dean pick between the two. Dean picks Sam and asks if there is a way to remove Sam's memories from hell. Death tells Dean he can't remove the memories, but he can put a wall up in Sam's mind. Before Dean can thank him, Death mentions that Dean has to win a wager in order for Death to get Sam's soul back. Dean, annoyed by the sudden complication, rolls his eyes and asks what the bet is. Death angrily walks straight up to Dean, who is visibly frightened, and tells him not to be rude. He then explains the wager: Death tells Dean to get the ring, put it on, and be him for a day. If Dean manages to go 24 hours as Death, Sam's soul will be returned, but if Dean takes off the ring before the time is up, he loses.
With no option other than to trust Death, Dean goes to get the ring and becomes Death for a day. Ultimately, by trying to do good, Dean ends up causing the death of an innocent nurse, and is forced to take the ring off and lose the bet to stop a man from killing other innocents in his grief. Dean realizes that escaping Death does more bad than good.
Back at Bobby's place, Dean and Death meet again. Dean admits that he understands how escaping the natural order messes more things up than it fixes. Death asks if Dean would do the same thing again knowing what Dean now knows, and Dean says no, he wouldn't. Death reveals his true intention behind giving Dean his ring; to teach Dean a lesson. Death tells Dean that messing up the natural order is hard when you're the one that has to clean it up. Dean thinks on this and asks if the wager was rigged from the beginning. Death doesn't answer Dean, but takes back his ring as he gets up and tells Dean that he going to hell to get Sam's soul. Dean is surprised at this and asks why Death would do this for him; Death responds by informing him that he wouldn't do it for Dean or Sam's sake because he considers them major disruption of the natural orders who cause problems on a global scale for him, but they are digging at something and he wants them to keep looking. Before he leaves, he gives Dean a hint, and tells Dean to keeping digging because they're getting close to the truth. Death says it's something "about the souls".
So Death goes to get Sam's soul and Dean rushes to the panic room. Dean watches as Death puts Sam's soul back into place. Sam screams for Death to get away from him, but Dean trusts Death and watches from the side.
|“|| Fried pickle chip? Best in the state."|
"That easy to soothe me, you think?
— Dean and Death
in Meet The New Boss
Since Castiel's power through all of Purgatory's souls, Dean desperately searches for a way to stop him, and initially finds nothing. Remembering what Death told him about one day killing God, Dean suggests they summon Death. With the help of Sam, Bobby and Crowley, they summon Death and bind him. Death is not too happy about being summoned or bound. Dean attempts to appease Death by offering him some fried pickle chips. This does not work and Death tells Dean that he can't be calmed like that. Death assumes that he was bound because of Sam's hallucinations, he wasn't going to do anything; "one wall per customer". Dean, who hadn't even known about Sam's problems, was shocked at the revelation, but refuses to unbind Death.
Dean informs Death that they need him to kill God. Death is openly surprised at this, to the point of asking them to repeat the statement. When Bobby nervously tells him that he heard right, Death asks why they assumed he could do that, and Dean reminds Death about how Death previously mentioned that he could kill God. Death asks why he should, and then Castiel appears. Castiel announces he will now kill Dean and Sam, only to have Dean tell him he can't because they had Death bound and wouldn't die even if God Himself tried to kill them. Realizing what Dean was talking about, Death refers to them as protozoa and calls Castiel a "mutated angel". Death and Castiel quickly start arguing, with Death mocking Castiel and warning about the Leviathans. Castiel, angered, confronts Death as nothing more than a fly swatter, to which Death responds, "Destined to swat you I think. Please, Cass, I know God, and you, sir, are no God." Nervous about the escalating argument, Dean quickly orders Death to kill Castiel. Death raises his hand to do so but Castiel quickly breaks the binding and flees. Death dryly notes how quickly Castiel left before sitting down in an armchair and eating the chips Dean got him.
As he eats, Sam, Dean, and Bobby have a silent conversation in which Sam frantically tries to get Dean to say something to Death. Dean is clearly reluctant, due to his words. When he finally attempts to speak, Death immediately orders him to shut up, and angrily snaps that he doesn't exist just to help Dean. Death angrily reminds Dean that he had warned Dean about the souls when they last met, and because Dean didn't listen things had gotten very bad. Dean responds by saying he did his best, and tells Death that he should find someone better next time, and Death informs him that he'll help a better planet from now on, and begins to walk out.
As he is leaving, Sam stops him and asks for help, saying that Death has to care somewhat about what happens to them. Death flatly informs Sam that he doesn't care at all, but admits that he finds Castiel's arrogance annoying. He tells Dean he needs to get Castiel to return the souls to Purgatory. When asked how to convince Castiel, Death flatly tells Dean to "figure it out." Bobby tells Death that another eclipse won't be in for a while, but Death tells him he will make another in a few days. He tells Dean not to thank him, but to clean up his mess. He starts to leave, but then stops, and without turning around, he says coldly "Try to bind me again, you'll die before you even start." He then thanks them for the pickle chips and leaves.
Death and Dean don't interact at all here, but Death does interact with Gadreel a little who's shapeshifted into Dean. Being who he is, Death knew exactly who and what he was, but said it was Sam's decision on if he wants to go or stay.
After realizing the Mark of Cain is pushing him too far, Dean summons Death to kill him, believing that only Death can permanently kill him with the Mark of Cain on his arm. Dean personally makes Death Mexican food which Death is shown to enjoy. Death tells him even he can't kill Dean but he can remove the Mark if Dean will pass it onto someone else first.
Death explains the history of the Mark and how it binds the Darkness and needs to be on someone to keep it bound. He offers to send Dean somewhere so far away he won't be a threat anymore. However, he demands Dean kill Sam as the price so Sam won't be able to get him back. Dean agrees and Death watches as the brothers confront each other. After Sam finally agrees to die for the greater good, Death gives Dean his scythe to do the job, telling Dean that if Dean doesn't kill Sam, he will. Reminded of how good he is and his love for his family, Dean turns the scythe on Death himself at the last moment, impaling him through the side and killing him. Death, as stoic as usual, is only mildly shocked before he crumbles to dust. Dean is left somewhat stunned that he actually killed Death.
Although Dean killed Death, as a result of Dean's actions the reapers, notably Billie, wish to punish them for their actions.
Dean finds that Billie has taken Death's place and she mentions him killing her predecessor.