In 1860, when Drusilla was about 18-to-24 years of age, she was a beautiful young Catholic woman who lived with her parents and sisters in London, England. Drusilla was "blessed" with foresight, and was capable of occasionally foretelling the future, especially tragic situations. However, she believed this to be an evil affliction and wished to enter a nunnery to cleanse herself of them. Darla saw Drusilla and showed her to Angelus. Darla knew about Drusilla's psychic abilities and believed it would be in their best interests to choose her as their next victim. Angelus, however, sensed her purity and became obsessed with destroying her, as Drusilla had the potential for sainthood.

Angelus harassed Drusilla for a long time, damaging her fragile mental health. Often in the guise of a priest, he would consult with her the matters of her visions, playing cruel mental games whenever she sought sanctuary. Angelus then tortured and killed Drusilla's entire family, causing her to leave for a convent in Prague. On the day she was to take her holy vows, Angelus made her watch as he killed every person in the convent, and engaged in sexual relations with Darla. The trauma of Angelus' atrocities drove Drusilla insane, and Angelus chose to turn her into a vampire, as he considered her a masterpiece, a testament of his talent.

After being sired, Drusilla, now a predator with a childlike sexuality, joined Angelus and Darla on their murderous travels. In 1880, Drusilla sired the young poet William, who joined the group. William, later known as "Spike," and Drusilla shared an intimate relationship, though Angelus continued to engage in sexual relations with her, mostly to annoy William.

When Angelus is cursed with a soul and becomes Angel, Spike and Drusilla (unaware of the ensoulment) go their separate ways from Darla and Angel. At some point before their arrival in Sunnydale in late 1997, Drusilla is attacked and severely injured by an angry mob in Prague, leaving her in a weakened and frail condition. Spike cares for her, and the couple decide to travel to the Hellmouth in hopes that its energy will help to restore Drusilla's strength and health.

Drusilla's story before her appearance in Sunnydale unfolds in flashbacks scattered among numerous episodes of both Buffy the Vampire Slayer and Angel; they were not presented in chronological order. A guide to finding the flashback or flashbacks to a particular event is at "List of Buffyverse historical flashbacks".

They arrive in Sunnydale (in the episode "School Hard"), and Spike plots the downfall of the current Slayer, Buffy Summers. When he discovers that Drusilla can be cured by the blood of her sire, Spike captures Angel and allows Drusilla to torture him until it was time to perform the ritual. Although Buffy and her friends save Angel, the ritual is successful. Drusilla, fully restored, now takes care of Spike, who has been temporarily crippled by Buffy's attack. When Angel reverts to Angelus, he re-joins the couple. Drusilla soon kills Kendra Young by hypnotizing her and slicing her throat. Kendra is the only known Slayer to be killed by Drusilla.

Drusilla is delighted by Angelus' determination to destroy the world and encourages his ongoing sexual attention; both dynamics strongly disturb Spike, who wants Drusilla to himself again and does not particularly want the world to end. Spike decides to help Buffy save the world in exchange for his and Drusilla's safe passage from Sunnydale, much to Drusilla's dismay. She resists his betrayal of Angelus and he attacks her, ultimately carrying her unconscious body from the fray.

Drusilla and Spike flee to South America, where Drusilla becomes disillusioned with their relationship. Spike's alliance with the Slayer, combined with her skills of foresight and perception, prove to her that Spike is now tainted (not "demon enough" for her), and that he is developing feelings for Buffy. Drusilla breaks up with Spike, and he rejects her offer to remain friends.

Drusilla does not reappear until 2001, when Wolfram & Hart bring her to Los Angeles to re-sire Darla, who had been resurrected as a human. Drusilla, who loves Darla like a parent, genuinely believes she is doing Darla a favor by siring her, and is puzzled by Darla's brief rage before her renewed vampire nature kicks in. Reconciled, the two wreak havoc in the city until Angel sets them on fire. The two go underground to heal, but Drusilla, now the older vampire, leaves Darla, who is then protected by Lindsey McDonald. Oddly Darla sired Angel, who sired Dru making Darla Drusilla's grand-sire.

Drusilla returns to Sunnydale to persuade Spike to join Darla and herself in reforming their "family" unit. However, Spike threatens to stake her to prove his love for Buffy. Disappointed by her former love, Drusilla departs. Drusilla's current whereabouts and activities from then on, if she is still "alive," remain unrevealed.

Drusilla's madness is exhibited in her often-strange dialogue, spoken in thick Cockney accents. Her speech is peppered with non sequiturs; for example, like "Spike, do you love my insides? The parts you cannot see?". Her behavior is generally very girlish but is always accompanied by a dark, ironic twist. For instance, when she is happy, she will squeal and laugh like a young child, but she is happiest when committing torture, hunting humans, or witnessing mass-destruction. She also loves flowers and cute animals, but is not sane enough to care for them. Every living thing she owns is neglected and eventually dies of starvation or thirst.

In 2002, the First Evil impersonates Drusilla in a bid to finally tip Spike over the edge of the mental cliff.