- The Origin: Lothos, a vampire king in Los Angeles who has killed numerous Slayers in the past, and now has his eyes set on Buffy.
- Season 1: The Master, the—um—master of an ancient order of vampires, who seeks to escape his prison and open the Hellmouth.
- Season 2: Spike and Drusilla, who come to Sunnydale hoping to find a way to heal the latter's sickness. They're joined halfway through (and Demoted to Co-Dragons) by Angelus, who lost his soul and now seeks to destroy Buffy—partially for making him feel human as Angel, mostly just for shits and giggles.
- Season 3: Mayor Richard Wilkins, an immortal sorcerer who wants to become a demonic Old One. New Slayer Faith serves as The Dragon, going through a bit of Sanity Slippage that leads to her becoming more violent and sadistic.
- Season 4: No antagonist is particularly prominent in the first half of the season—Spike returns, but it's abundantly clear he's not as much of a threat as he used to be. Eventually the Initiative, a government program investigating the magical happenings of Sunnydale under the leadership of Professor Walsh, takes center stage... before Walsh's monstrous creation Adam kills her halfway through, teams up with Spike, and starts his own plan to create an army of demon-human-cyborg hybrids like him.
- Season 5: Glorificus, a Hellgod who seeks the Key in order return to her home dimension (not caring that doing so would rip apart reality), and in the meantime is eating people's sanity to maintain her own.
- Season 6: The Trio, a group of recurring nerds (Warren, Jonathan, and Andrew—Tucker's brother) who have teamed up to take over Sunnydale and generally be annoyances. Warren turns out to be the worst of them as he murders his ex-girlfriend, forces the other two into continuing their supervillain exploits when they start getting cold feet, and kills Tara while trying to shoot Buffy. This comes back to bite him as he's soon killed by an enraged Willow, who's been an Unwitting Instigator of Doom throughout the season under an addiction to dark magic and becomes the Final Boss as she decides to end the world in a fit of nihilistic grief.
- Season 7: The First Evil, who tries to take advantage of the imbalance caused by Buffy's resurrection to wipe out the Slayer line. Caleb, a misogynistic Serial Killer preacher, is brought in as The Dragon late into the season.
- Season Eight: Twilight, a mysterious villain with Super-Strength and Flight that forms a Legion of Doom to oppose the new Slayer army. He's eventually revealed to actually be Angel, trying to organize all of the threats to Buffy under the reasoning that they would cause greater damage if allowed to run amok. Unfortunately he's also been Brainwashed and Crazy by a sentient dimension, also named Twilight, that seeks to birth itself through Buffy and Angel.
- Season Nine: A Big Bad Duumvirate between Ax-Crazy rogue Slayer Simone Doffler and the magic absorber known as the Siphon, Severin, who blames Buffy for the emergence of the zompires. Simone attempts to become a "slaypire" by raising the Old One progenitor of vampires, Maloker, while Severin has a Heel–Face Turn after realizing he can't use Illyria's powers to prevent Twilight and sacrifices himself to create a new Seed of Wonder.
- Season Ten: D'Hoffryn (after a brief Big Bad Ensemble with the Sculpter, the Mistress, and the Glutton), taking advantage of the new and flexible rules of magic to amass more power for himself.
- Season Eleven: Joanna Wise, the mastermind behind the Pandora Project and the dragon attack, who wants to take all the world's magic for herself.
- Season Twelve: Harth Fray, having traveled from the future and gathered an army of demons (including the Mayor) to steal the Slayer powers for himself.
- Season 1: Wolfram & Hart, a law firm that serves as a front for powerful demons known as "The Senior Partners" who have influenced humanity towards violence and evil since the very first cave man clubbed his neighbor. As the Partners are unseen Greater-Scope Villains throughout the entire show, they're represented in the first season primarily by Lindsey McDonald, Lilah Morgan, and Lee Mercer. The last two episodes introduce their superior and the head of the firm's Special Projects Division, Holland Manners, who kills Lee and tempts Lindsey into staying on their side.
- Season 2: Darla, having been resurrected by Wolfram & Hart to screw with Angel's head. When she tries to pull a Heel–Face Turn halfway through the season, Drusilla is brought in to turn her back into a vampire—which turns out to be a bad idea, as the two proceed to kill Manners before threatening Lilah and Lindsey (who eventually has a Heel–Face Turn of his own) into being their moles at the firm. The Pylea storyline that closes the season has Silas as the Arc Villain, with Wolfram & Hart serving as Greater-Scope Villains to him too.
- Season 3: A Big Bad Ensemble between Wolfram & Hart, represented mainly by Lilah with Linwood Murrow as her new superior and continuing their efforts to screw with Angel whenever the opportunity presents itself; Sahjhan, an intangible and time traveling demon that hates Angel for... some reason (it's revealed in the second half of the season that he's destined to die to Angel's son); and Daniel Holtz, an 18th century vampire hunter who is brought to the present by Sahjhan after his family was killed by Angelus. Unfortunately for Sahjhan's plans, killing Angel is the last thing on Holtz's mind, as he proceeds to kidnap Angel's son Connor and raises him to hate his father in a time-displaced hell dimension.
- Season 4: Jasmine, a fallen member of the Powers That Be who orchestrated a majority of the series' events to ensure her own birth. She proceeds to try and create paradise—by brainwashing everyone in Los Angeles. Oh, and she eats people. She's also served by her Co-Dragons the Beast (who serves as Jasmine's muscle in the first half of the season, killing most of the staff of Wolfram & Hart to set things up for her birth) and Angelus (who is freed from his curse in order to get more information on the Beast, escapes and is forcibly recruited into the Evil Plan, betrays the Beast the first chance he gets, and proceeds to go on a rampage in the time leading up to Jasmine's birth).
- Season 5: No threat is immediately apparent, as Angel and co. are now running Wolfram & Hart. Lindsey makes a return and tries to kill Angel, but is quickly foiled once his presence is revealed. The Circle of the Black Thorn, agents of the Senior Partners composed of minor characters throughout the season that Lindsey was trying to impress, are revealed late into the season, shortly after the introduction of the Partners' child/liaison/enforcer, Marcus Hamilton.
- After the Fall: Gunn, having been turned into a vampire and believing that he can save the world... though still doing normal vampire things like eating people. He eventually tries to coerce Illyria into rewinding time to before Los Angeles is dragged down to Hell, but she goes a step further and decides to just unmake reality (not that he minds). The Senior Partners could also count for, you know, dragging all of Los Angeles down to Hell, but besides sending an army of conduits they still remain The Unseen.
- Season Nine: Whistler, revealed to be responsible for Twilight and, after a bit of Sanity Slippage from the destruction of the Seed, tries to bring magic back to the world by creating a magic plague that would kill millions.
- Season Ten: Archaeus, the demon progenitor of the Master's vampire line, hoping to sway the sentient magic of Magic Town to his side. Drusilla also makes a return as The Dragon, gathering an army for him.
- Season Eleven: Some... plant... demon... zombie insect plague... thing created by Angel, Fred, and Illyria time traveling in an effort to stop said thing from emerging. An argument could be made for Angel being the Big Bad, his regrets and attempts to change his past causing the paradox that births the creature—regrets not helped by the past versions of Angelus and Darla they run into halfway through.
Other:
- Fray: Harth, Melaka's twin brother who inherited the Slayer visions and was turned into a vampire by Icarus, using the knowledge from the visions to try and bring demons back to earth.
- Spike IDW series: Wolfram & Hart, with the Senior Partners themselves descending in a gambit to escape into another dimension before Twilight arrives. Drusilla and a serial killer named John, who lost his soul to Spike and wants it back, are brought in as muscle but quickly go rogue as they pursue their own goals and vendettas.
