The White Devil opens with Lodovico, a murderous Italian count, being informed by his two friends Gasparo and Antonelli of his banishment from Rome. Lodovico is enraged, but he agrees to leave, and gives his friends money to work towards securing his pardon.
Elsewhere, the Duke of Brachiano visits the house of Camillo with the intention of seducing his beautiful wife, Vittoria Corombona. Aided by her social-climbing brother Flamineo and her Moor servant Zanche, Vittoria allows Brachiano to secretly visit her. He gives her a jewel, and she tells him of a dream she had wherein her husband and his wife tried to kill her. Brachiano promises to protect her. Suddenly, Vittoria's mother, Cornelia, steps out of the shadows. She criticizes Brachiano's and Vittoria's affair, cursing them and her family.
In Act 2, Francisco de Medici, the Duke of Florence, welcomes home his sister and Brachiano's wife, Isabella. Despite her husband's infidelities, Isabella pleads with Francisco to be kind to Brachiano. She leaves, and Brachiano enters. Francisco recruits Cardinal Monticelso to chastise Brachiano for his infidelities. Threats of war between Brachiano and Francisco are made. After Giovanni, Isabella and Brachiano's son, comes on stage, Francisco and Brachiano seem to reconcile, and their threatening talk of war subside. Monticelso and Francisco leave, and Isabella approaches Brachiano. He quarrels with her despite her placating nature, and he cruelly divorces her. Isabella is unhappy, but she offers to take responsibility for instigating the divorce since she has justifiable cause (his infidelities), and he doesn't. Monticelso and Francisco re-enter to find Isabella yelling at Brachiano for his involvement with Vittoria, and for divorcing him. They scold her for being a jealous woman, and she leaves.
Meanwhile, Doctor Julio plots with Flamineo and Brachiano on how to best murder Isabella and Camillo. Monticelso and Francisco address the newly arrived Camillo, who is also Monticelso's nephew. They send him off to fight pirates so that they may secretly observe Brachiano's and Vittoria's behavior while he is away.
Later, Brachiano and a conjurer meet in the middle of the night. Brachiano asks him to reveal the particulars of the two planned murders, and the conjurer draws up silent shows of the simultaneous events. In Padua, Doctor Julio and his assistant Christophero poison the lips of a painting of Brachiano. During her nightly devotions, Isabella kisses the lips, and quickly dies. Meanwhile, at Camillo's house, a night of drinking and carousing leads Camillo and Flamineo to compete in vaulting. While all the other revelers are out of the room, Flamineo grabs Camillo and breaks his neck, making his death look like a vaulting accident. Pleased with the visions, Brachiano leaves.
Monticelso and Francisco suspect foul play in Camillo's death, and they put Vittoria on trial for it. Although they lack evidence that she committed the murders, they plan to ruin her character and secure conviction that way. Flamineo and Marcello argue over Flamineo's illicit actions, while various ambassadors arrive to act as judges in the trial. Brachiano unexpectedly shows up to the trial, and Vittoria dismisses her lawyer because he refuses to speak plainly. Monticelso then takes on the role of both prosecutor and judge, and repeatedly calls Vittoria a whore. Vittoria indignantly defends herself, and her bravery wins over the admiration of the ambassadors. Despite this, Monticelso sentences her to a "house of convertites," a place for penitent whores. Vittoria rages against Monticelso, crying as she is taken away that he has raped Justice. After the trial, Brachiano re-enters and murmurs a few mysterious words to Francisco. Giovanni then clarifies the mystery: Isabella is dead. Flamineo is upset with the trial's verdict, and accuses Monticelso of being corrupt. Lodovico enters, and the two murderers exchange insults before Antonelli reveals that Lodovico's banishment has been lifted. Flamineo hits Lodovico for calling Vittoria a whore, and everyone disperses.
Secretly seeking revenge for his sister's death, Francisco borrows Monticelso's "black book" of criminals, looking for a hitman. Isabella's ghost appears to him, but he dismisses it, thinking it simply a symptom of his melancholy. He writes a fake love letter to Vittoria in order to enrage Brachiano.
Later, while Flamineo is talking with the matron of the house of convertites, Francisco's servant delivers the love letter. When Brachiano reads it, he becomes wildly jealous of Vittoria, and calls her a whore. Although Vittoria denies any relationship with Francisco, Brachiano breaks off his relationship with her. When he sees her sobbing, however, he has a change of heart, believes her, and resolves to break her out of her prison.
Meanwhile, the papal election is underway, and Lodovico stands guard outside of the conclave to prevent bribery. Soon, the Cardinal of Arragon announces the new Pope: Cardinal Monticelso. During the pageantry, a servant informs Francisco that Vittoria, Brachiano, Flamineo, and Giovanni have fled the city. Outwardly outraged, Francisco inwardly admits that this has been his plan all along. He gets Monticelso to excommunicate Brachiano and Vittoria, and hires Lodovico to murder them. After Francisco leaves, Monticelso asks Lodovico why Francisco pushed for his pardon. Lodovico reveals the murder plan, which Monticelso outwardly disapproves of but secretly facilitates through money sent to Lodovico. Lodovico leaves on his mission, encouraged by the support of both Francisco and the new Pope.
Meanwhile, Vittoria and Brachiano have married and are now holding court in Padua. Mulinassar, a mysterious Moor, has recently arrived at their court, along with two Capuchin monks. Brachiano welcomes them, but when he leaves the stage, the men reveal their true identities. Francisco has disguised himself as a Moor, and Lodovico and Gasparo are accompanying him.
Flamineo speaks with Hortensio, a member of Brachiano's court, and reveals that he is sleeping with Zanche, Vittoria's Moor servant. Zanche has a brief fight with Flamineo, during which Cornelia flies in and attacks her. Marcello and Flamineo fight over Flamineo's improper relationship with Zanche, and in response to Marcello's criticism, Flamineo kills him. Brachiano is forced to try Flamineo for murder.
While they talk, Lodovico poisons the mouthpiece of Brachiano's helmet. Soon after, during the celebratory wedding games, Brachiano realizes that he has been poisoned. Gasparo and Lodovico, disguised as monks, are left alone to preside over his last rites, but they instead curse and strangle him. Zanche, now in love with the supposed Moor Mulinassar (really Francisco), admits to him how Isabella and Camillo died, as well as that she and Vittoria are running away that night.
Now in charge, Giovanni banishes Flamineo from the court. While leaving, Flamineo encounters his brother's funeral, and his distracted mother. After witnessing Brachiano's ghost, Flamineo decides to kill his sister in order to set everything right.
Elsewhere, Francisco and Lodovico meet, and Lodovico tells Francisco to leave the court so that he is not implicated in the murders. Hortensio overhears their conversation, and alerts Giovanni and the armies.
Flamineo finds Vittoria and Zanche, and demands money. He reveals that Brachiano made him promise to kill Vittoria if he ever died. The women agree to a three-way suicide pact, with Flamineo dying first. They break their promise, however, and shoot only him. Flamineo is outraged, and reveals that the gun was not loaded with bullets. He springs up to kill them, but Lodovico, Gasparo, Carlo and Pedro barge in. The men stab Flamineo, Vittoria, and Zanche to death. However, Giovanni and his guards storm on stage at the moment and capture the four murderers.