Season One 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 Harris and Willow Rosenberg, who help her fight evil through the series, but they must first prevent The Master, an ancient and especially threatening vampire, from opening the Hellmouth and taking over Sunnydale.

The emotional stakes are raised in Season Two. New vampires Spike and Drusilla (weakened from a mob in Prague, which presumably caused her debilitating injury), come to town along with the new slayer, Kendra Young, who was activated as a result of Buffy's brief death in the Season One finale. Xander becomes involved with Cordelia, while Willow becomes involved with witchcraft and Daniel "Oz" Osbourne, who they soon find out is actually a werewolf. Buffy and the vampire Angel develop a relationship over the course of the season, but after they sleep together, Angel's soul, given to him by a curse, is lost and he once more becomes Angelus, a sadistic killer. He torments much of the "Scooby Gang" throughout the rest of the season and murders Jenny Calendar, a gypsy that had been sent to make sure that the curse that gave Angel his soul was never broken, as well as many other innocents. Buffy is forced to kill him (right after Willow restores his soul) and leaves Sunnydale, emotionally shattered.

After attempting to start a new life in Los Angeles, Buffy returns to town in Season Three. Angel is resurrected, but after he and Buffy realize that a relationship between them can never happen, he leaves Sunnydale at the end of the season. Giles is fired from the Watcher's Council because he had developed a "father's love" for Buffy, and towards the end of the season Buffy announces that she will also no longer be working for the council. Early in the season she is confronted with an unstable Slayer, Faith Lehane, who was called up after Kendra's death near the end of season 2, as well as affable Sunnydale Mayor Richard Wilkins, who has plans to become a giant snake demon on Sunnydale High's Graduation Day. Although she works with Buffy at first, after accidentally killing a human, Faith becomes irrational and sides with Mayor Wilkins, although she is placed into a coma after a fight with Buffy. At the end of the season, Buffy and the entire graduation class defeat Mayor Wilkins by blowing up Sunnydale High, killing him in the process.

Season Four 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 The Initiative, a top-secret military installation based beneath the UC Sunnydale campus. They implant a microchip in his head which prevents him from harming humans. He reluctantly helps the Scooby Gang throughout the season and eventually begins to fight on their side after learning that he can harm other demons. Oz leaves town after realizing that he is too dangerous as a werewolf, and Willow falls in love with Tara Maclay, another witch. Buffy begins dating Riley Finn, a grad student whom she later realizes is a member of The Initiative. Although appearing to be a well-meaning anti-demon operation, it is realized that it had more sinister plans as its demon/Human/computer hybrid secret project, Adam, escapes and begins to wreak havoc on the town. The season also marked the first year in which Joss Whedon oversaw other TV series.

During Season Five, a younger sister to Buffy, Dawn, suddenly appears in Buffy's life, and although she is new to the series, to the characters it is as if she has always been there. Buffy is confronted with Glorificus (Glory), an exiled hell-God that is searching for a "Key" that will allow her to return to her Hell dimension and in the process would blur the lines between dimensions and unleash Hell on Earth. It is later discovered that the Key's protectors had turned the Key into Human form as Buffy's sister Dawn, concurrently implanting everybody with lifelong memories of her. The Watcher's Council aids in Buffy's research of Glory, and she and Giles are both reinstated by the Council. Glory later discovers that Dawn is the key and kidnaps her. Buffy sacrifices herself to save Dawn and prevent the portal to the Hell dimensions from opening. Riley leaves early in the season after deducing that Buffy does not love him and joins a military demon-hunting operation, while Spike, still implanted with the Initiative chip, realizes he is in love with Buffy and continually helps the Scoobies in their fight. Buffy's mother, Joyce, dies of a brain aneurysm, while at the end of the season, Xander proposes to Anya.

At the beginning of Season Six, Buffy's friends resurrect her through a powerful spell. Although believing that they had taken her out of Hell, it is later revealed that she was in Heaven during her death and she falls into a deep depression for most of the season. Giles returns to England after realizing that Buffy has become too reliant on him, while Buffy takes up a fast-food job for money and develops a secret, mutually abusive relationship with Spike. Dawn suffers from kleptomania and feelings of alienation, Xander leaves Anya at the altar, after which Anya once again becomes a vengeance demon, and Willow becomes addicted to magic, causing Tara to temporarily leave her. They also begin to deal with The Trio, a group of nerds led by Warren Mears who use their technological proficiency to attempt to kill Buffy and take over Sunnydale. Warren is shown to be the only competent villain of the group and, after Buffy thwarts his plans multiple times and the Trio breaks apart, he comes unhinged and attacks Buffy with a gun, killing Tara in the process. This causes Willow to descend into darkness and unleash all of her dark magical powers, killing Warren. Giles returns to face her in battle and infuses her with light magic, tapping into her remaining humanity. This causes Willow to attempt to destroy the world to end everyone's suffering, although it eventually allows Xander to reach through her pain and end her rampage. At the end of the season, Spike leaves Sunnydale and travels to see a demon and asks him to "return him to what he used to be" so that he can "give Buffy what she deserves". After passing a series of tests, the demon restores his soul.

During Season Seven, it is revealed that Buffy's revival at the beginning of season 6, and the instability caused by it, has allowed the First Evil to begin tipping the balance between good and evil. It begins hunting down and killing all of the inactive Potential Slayers, and begins raising an army of ancient, powerful Turok-Han vampires. After the Watchers' Council is destroyed, Giles arrives with a number of the Potential Slayers, and over the course of the season an increasing number of Potential Slayers takes refuge in Sunnydale. Faith returns to help fight the First Evil, and the new Sunnydale High's principal, Robin Wood, also join the cause. The Turok-Han vampires and a sinister preacher known as Caleb begin causing havoc for the Scoobies as the year goes on. Throughout the season, the Hellmouth became overly active and the increasing amount of supernatural phenomena caused everyone to leave the city. At the end of the season, the Scoobies descend into the Hellmouth while Willow uses a spell that activates all of the Potential Slayers, granting them Slayer powers. Angel returns to give Buffy an amulet, but Buffy instead gives the amulet to Spike, who has returned to Sunnydale. Anya, who has returned to being Human, dies in the fight, as do some of the Potential Slayers. At the end of the fight, Spike uses the amulet, which channels the power of the sun and kills all of the vampires in the Hellmouth, apparently incinerating Spike in the process. This causes the Hellmouth to collapse, and the entirety of Sunnydale collapses into the crater with it, just as everyone manages to escape.