The first season exemplifies the "high school as hell" concept. Buffy Summers has just moved to Sunnydale after burning her old school's gym and hopes to escape her Slayer duties. Her plans are complicated by Rupert Giles, her new Watcher, who reminds her of the inescapable presence of evil. Sunnydale High is built atop a Hellmouth, a portal to demon dimensions that attracts supernatural phenomena to the area. Buffy meets two schoolmates, Xander and Willow, who will help fight evil through the series, but they must first prevent an ancient and especially threatening vampire from opening the Hellmouth and unleashing Hell on Earth.

The emotional stakes are raised in the second season. New vampires, Spike and a weakened Drusilla, come to town along with the new Slayer, who was activated as a result of Buffy's brief death in the first season finale. Xander becomes involved with Cordelia, while Willow becomes involved with witchcraft and a young werewolf named Oz, both of which make her more confident. Buffy sleeps with her vampire lover Angel. Consequentially, she unwittingly removes his cursed soul as a result. He once more becomes Angelus, a sadistic killer. Buffy is forced to kill him, and leaves Sunnydale, emotionally shattered.

After attempting to start a new life in Los Angeles, Buffy returns to town in the third season. Angel is resurrected, but leaves Sunnydale (at the end of the season) so Buffy will have a normal life. She is soon confronted with an unstable Slayer, and an often affable but definitely evil mayor's plans for Graduation Day.

The fourth season sees Buffy and Willow enroll at UC Sunnydale while Xander joins the workforce and begins dating Anya, a former vengeance demon. Spike returns as a series regular and is abducted by a covert military force; they implant a microchip in his head which prevents him from harming humans. Oz leaves town after deciding he's too dangerous and Willow falls in love with Tara Maclay, another witch, while Buffy begins dating a grad student who is a member of The Initiative, a top-secret military installation based beneath the UC Sunnydale campus. It appears to be a well-meaning anti-demon operation, but its secret project goes horribly wrong. The season also marked the first year in which Joss Whedon oversaw other TV series.

During the fifth season, a younger sister suddenly yet seamlessly appears in Buffy's life and an exiled Hell-God searches for a "key" that will allow her to return to her home dimension. The "key" has been turned into human form as Buffy's younger sister Dawn. The Hell-God eventually discovers the truth and kidnaps Dawn; Buffy sacrifices herself to save Dawn and prevent Hell from spreading on Earth. During the season, Xander and Anya become engaged, and Spike realizes he is in love with Buffy.

Buffy's friends resurrect her through a powerful spell in the sixth season. Buffy returns from Heaven deeply depressed and finds a job at a fast food restaurant while conducting a secret, mutually abusive affair with Spike that later leads to him attempting to rape her. Plagued with remorse, he undergoes a series of trials and is awarded with a soul so he can "give her what she deserves". Her friends are unaware of her inner turmoils as they face their own troubles: Xander leaves Anya at the altar, and Willow becomes addicted to magic. When Tara is killed by an unhinged Warren Mears, Willow descends into darkness and begins a rampage that nearly causes the end of the world. In the end it is Xander who reaches through her pain and stops her from destroying the world.

The instability caused by Buffy's revival enables the First Evil and a sinister preacher to amass an army of powerful vampires against humankind during the seventh season, while simultaneously seeking out and killing every currently-unactivated Potential Slayer. Willow invokes a spell that activates all the "Potentials" in the world. After an epic battle, an amulet worn by Spike channels solar energy through the battlefield, killing all of the vampires and apparently incinerating Spike. As the Scoobies flee Sunnydale, the town collapses into a crater, its Hellmouth destroyed.