Michael: Now, at first, I thought I'd do it better. Show Him. Be more God than God. But now... I just want to burn every one of His little worlds until I catch up to the old man.
Castiel: And then what?
Michael: Even God can die.
Castiel: And then what?
Michael: Even God can die.
- Lucifer was once a prideful Archangel who tortured the below-mentioned Lilith into being the first demon, corrupting human souls, for which he was locked in hell. Enacting the misery that befell the Winchester family through his child Azazel, Lucifer achieves freedom in the 5th season and causes mass loss of life across the world, seeking to wipe out humanity before he intends to destroy the demons as well. Later freed from his cage to assist God and the Winchesters against God's sister, the Darkness, Lucifer later simply begins causing random mayhem and destruction for fun before attempting to become the new God. Failing miserably at the job, Lucifer supposedly begins to connect with his son Jack, but when Jack sees him for the egotistical monster he really is, Lucifer steals Jack's powers and decides to annihilate all life in the universe and remake it in his own image, even trying to force Sam and Jack to choose which of them will kill himself first to give the other a vague chance at stopping Lucifer. While trying to paint himself as a tragic figure, Lucifer is an egotistical brat throwing a temper tantrum, whose every redeeming quality is steadily stripped away until he is shown to be a selfish sociopath with a god complex who utterly rejects love and compassion in favor of cruelty and egotism.
- Lilith, from seasons 3 and 4, is the oldest demon in existence, and one of the worst. She massacres a police station, killing everyone that Sam and Dean had just finished saving, uses her position as the holder of Bela's contract to try and force her to kill Sam, and keeps a personal chef on hand to prepare human infants for her to eat. Lilith also has a thing for possessing little girls, destroying their families from the inside out for her own personal amusement. In the season 3 finale, she holds a family hostage, killing the grandfather for making her mad, and has Dean dragged off to Hell, laughing the entire time. Reappearing in season 4, Lilith reveals that her current plan is to free Lucifer, bringing about the The End of the World as We Know It. When she discovers that freeing Lucifer will ensure her death, she tries to back out, offering to put off the apocalypse if Sam and Dean will let her kill them. Defeated by Sam in the season 4 finale, Lilith goads him into finishing her, knowing that her death will result in the deaths of all humanity.
- Alastair, from season 4, is Hell's Grand Inquisitor, and assists the aforementioned Lilith in her attempts to free Lucifer. Feared by demons beyond even angels, Alastair is responsible for supervising all the torture of Hell's souls, eventually corrupting them into demons. Having spent a hundred years torturing John Winchester, Alastair brutally tortured Dean every day then healed the damage and starting again for thirty years. Broken, Dean agrees to torture other souls to stop his suffering, thus breaking the first of the seals imprisoning Lucifer. Hunting for Anna Milton, Alastair slit her parents' throats. When Ruby offers him Anna in exchange for sparing them Alastair captures and brutally vivisects Ruby with her own knife, beats Castiel senseless and scrambles Deans organs. To break another seal, he murders a Reaper and attempts to murder Tessa. Captured, Alastair gleefully psychologically tortures Dean, then brutally beats and attempts to banish Castiel, before finally being killed by Sam. Living only to cause suffering and enjoying every single moment of it, Alastair was one of the worst demons in the series.
- "Dick Roman", from season 7, is the leader of the Leviathans. Not content with simply lurking in the shadows to feed on humanity, he planted his minions in key positions, murdering and devouring every human in the way. Taking control of a major company, Roman began to place chemicals in corn syrup so humanity would be rendered helpless as cattle for the Leviathans to feed on. The Winchesters, who he knew could prove an issue, he framed for a nation-wide killing spree. Other monster species were seen as "competition," with Roman planning to exterminate them as well after manipulating them into helping him. A horrible boss even by the show's standards, Roman was known to devour his minions in a fit of rage or "bib" them: forcing them to devour themselves. Few villains on Supernatural have managed to inspire the same fear or hatred as Roman did, and his killing of Bobby Singer only deepened the hatred the Winchester brothers had for him.
- Whitman Van Ness, from season 7's "Of Grave Importance", was a former rich man turned murderer in the early 1900s. He slit the throats of numerous prostitutes who worked in his manor house, climaxing with the murder of his own fiancée and framing the caretaker Dexter O'Connor for everything, leading to Dexter being shot by the authorities. Following his death, Whitman became a very powerful spirit, and, to protect himself from the decay all ghosts suffer, began feeding off other spirits, effectively destroying them. Whitman spent decades killing countless people who came into his house, then used his powers to prevent their spirits from passing on; trapping his victims in constant terror of him whilst they all slowly decay into rotting mindless abominations so he could stay strong. Whitman also takes amusement from their horrific fate and enjoys lording his power over them. In the present he murders two teenagers who hide in his house, and then murders Sam, Dean and Bobby's old friend Annie Hawkins. A few nights later he murders two friends of the first pair of teenagers by crushing their hearts, adding all of them to his collection. When Dexter protested that he already had more than enough victims, Whitman drained him on the spot. Whitman's final act was to try and drain Bobby, before Sam and Dean burnt his bones.
- Abaddon, from seasons 8 and 9, proved herself to be as evil as any of her demonic predecessors. As one of the Knights of Hell, the first demons created by Lucifer, she was trained by Cain before he became The Atoner. Abaddon tricked Cain into murdering the human woman he had fallen in love with with the First Blade, earning his undying hatred. After centuries of serving under Hell's banner, in 1958 she kills a priest who was researching a demon cure. She possesses Josie Sands to infiltrate the Men of Letters, noting that Josie is in love with her partner Henry Winchester and therefore can hurt them more. Abaddon massacres the Men of Letters and follows Henry through a time portal into 2012, disposing of him after going back on a deal she made with Sam and Dean. When she discovers that Hell has been brought under the more pragmatic Crowley in her absence, she sets out to become Queen of Hell and promises her followers a new reign of terror. After Crowley regains his human emotions, Abaddon kidnaps his son Gavin and proceeds to torture him in front of his father. He caves in to her demands and helps her to defeat the Winchesters, but then she decides to kill them all anyway.
- Archangel Michael of the Apocalypse World, from seasons 13 and 14, is the utterly egocentric head of a genocidal regime that seeks to exterminate humanity, with few survivors. Seeking to leave the world to annihilate others, Michael tortures Lucifer from the main world to obtain his power and murders the archangel Gabriel when he attempts to defend humanity. Eventually possessing Dean, Michael decides on monsters as a "perfect" race, killing many in experiments to perfect them and unleashing them on hunters and innocent humans, even attempting to have Kansas City itself wiped out. Revealing his intentions and his anger at God, Michael intends on pursuing his creator to exterminate world after world and all life therein until he catches and kills God, remaining one of the most brutal and cruel angels ever encountered.
- FBI agent Terrence Clegg, from season 13's "Breakdown", is the notorious "Butterfly", and, despite being only human, is among the worst the Winchesters have faced. Having discovered that monsters exist, and exploiting their hunger for his own greed, Clegg kidnaps numerous humans before torturing and butchering them on a live broadcast before auctioning their body parts and organs off to monsters as food; he has done this for twelve years, racking up a body count of possibly hundreds. When Dean and Sam Winchester investigate Clegg's crimes, he kidnaps Sam and attempts to cut his heart out before auctioning him off to his monstrous clientele.