Angelus — Drusilla is sired by Angelus after he kills her entire family and drives her insane. As a vampire, she and Angelus have a sexual relationship, and she often refers to him as her "bad daddy." Their sexual relationship continued even after she sires Spike. When she and Spike later capture the ensouled Angel, Drusilla tortures him, reminding him of all the horrible things he did to her. After Angel loses his soul, they resume their intimacy, putting a strain on her relationship with Spike.

Spike — Drusilla was romantically involved with Spike for over a century. They were a devoted couple; while vampires do not usually experience love for one another, Spike and Drusilla did, as was noted by the Judge (who found their relationship to reek of humanity). They traveled around the world, keeping each other company and enjoying themselves. While Spike was single-mindedly devoted to her, Drusilla was never consistently faithful; she maintained a sexual relationship with Angelus despite Spike's obvious jealousy and discomfort, and (along with Darla) fornicated with The Immortal. She became disillusioned with Spike after he betrayed Angelus and allied himself with Buffy, and she perceived Spike's growing feelings for Buffy. Drusilla cheated on Spike with a chaos demon in South America before breaking up with him, sending him into an extended drunken depression.

The Immortal and Darla — Drusilla had a threesome with the Immortal and Darla, much to the dismay of both Spike and Angelus, who claimed that the girls "Never let them do that" (cf. "The Girl in Question").

Xander Harris — She had a crush on Xander when he accidentally put all the women of Sunnydale under a love spell (cf. "Bewitched, Bothered and Bewildered"). Drusilla relentlessly pursues him until he enters Buffy's house; she is unable to follow him in because she is not invited.

Rupert Giles — After Giles withstands significant torture at the hands of Angelus, Drusilla hypnotizes him and appears to his eyes as Jenny Calendar. She gently pries the necessary information from him, and kisses him for an extended period of time. Spike and Angelus protest the length of the kiss, and she notes that she had been "in the moment" (cf. "Becoming, Part Two").

Chaos Demon — After becoming disillusioned with Spike, Drusilla makes out with a Chaos Demon; he has no idea that she is seeing somebody, and is distressed when a jealous Spike arrives (cf. "Lovers Walk", "Fool for Love").