The White Devil begins on an odd note—the city of Rome banishes Lodovico, a depraved and murderous Count, who will be important in the story later, just not right now. At the moment, he's just going to complain about getting banished. The real main characters are introduced in scene two: Vittoria Corombona, an Italian noblewoman (who, nevertheless, is apparently poor), who is unhappily married to Camillo—the nephew (though also poor) of an important Cardinal, Monticelso. The scheming Duke of Brachiano—Paulo Giordano Orsini—plots to seduce Vittoria, with the help of her brother Flamineo.
Flamineo is a bit of a social-climber, and hopes this will help his advancement in the world. He's also a cold-blooded murderer (or will be soon) and a pessimistic arm-chair philosopher. Vittoria seems willing enough to be seduced, and asks Brachiano for protection from her husband and the Duke's own wife, since she had a dream where they were trying to bury her alive. The Duke promises to help—by killing both Camillo and his wife, though it's unclear if Vittoria fully gets this (though she seems to—probably even intends it). Also, quite awkwardly, Vittoria and Flamineo's Mom, Cornelia, overhears their conversation with the Duke, and yells at Flamineo for being such a vicious, murder-plotting schemer.
Brachiano has to deal with his highly suspicious wife, Isabella after he states that he doesn't love her and wants a divorce. Isabella remains pretty devoted to this creep and pretends to be enraged at Vittoria in order to make herself look jealous and throw suspicion off the Duke. Francisco de Medici, Isabella's brother, and Camillo's uncle (Cardinal Monticelso) want to make sure that the Duke doesn't get away with this whole divorce thing. But it's too late—the Duke has both his wife and Vittoria's husband killed. A corrupt doctor who specializes in poison helps arrange Isabella's death, and Flamineo breaks Camillo's neck and makes it look like a gymnastics accident.
Lacking evidence, but really angry, Francisco and Monticelso put Vittoria on trial for the murders—but they don't try Flamineo or Brachiano, the men who actually arranged the deed (Webster leaves the full extent of Vittoria's guilt a little ambiguous). After Monticelso delivers an incredibly aggressive and bitter courtroom attack on Vittoria for being a "whore," and Vittoria gives a spirited defense, she is sentenced to live out the rest of her life in "a house of penitent whores." In order to avoid any unpleasant questionings about his own guilt, Flamineo pretends to go mad. (It's a pretty philosophical and lucid kind of fake madness though).
After some initial jealousy and confusion caused by a fake love letter Francisco writes to Vittoria while she is in the house of "convertites," Vittoria escapes with the Duke to Padua and they get married. Meanwhile, Monticelso is low-key elected Pope (becoming Pope Paul IV), but that doesn't stop he and Francisco from scheming out a revenge plot, intending to use Count Lodovico—the dude from the beginning, who also was in love with Isabella and wants to kill the Duke for that reason—as their assassin.
Francisco infiltrates Brachiano's court in Padua, along with Lodovico and a henchman named Gasparo. Francisco is disguised as an important Moor (a person from North Africa), and the other two are disguised as Capuchin monks. Flamineo ends up murdering his own brother, Marcello—who confronts him about an affair Flamineo has been having with the Moorish maid, Zanche. This upsets Flamineo's mother, which upsets Flamineo—reminding him of his humanity (to some extent). Lodovico successfully poisons Brachiano and then strangles him just to speed things along, while pretending to minister the last rites to the Duke.
After being banished from Padua by Giovanni (Brachiano's son and successor) Flamineo goes to Vittoria, pretending that he aims to kill her and himself. When Vittoria fake agrees to kill herself, she uses the pistol Flamineo gives her to "shoot" him. But it turns out that it wasn't really loaded with bullets, and Flamineo—after making a fake death speech—was just testing her loyalty. But, although Vittoria thinks she's narrowly escaped death, she hasn't: Lodovico and Gasparo bust into the room and fatally stab her and Flamineo. They both give eloquent deathbed speeches. Then Giovanni and his officers enter the room, are horrified by the scene, and arrest Lodovico (who's still pretty pleased with himself) for committing these revenge murders. They drag him off to be tortured and killed. And they lived happily ever after.