As the play opens, Vindice is intent on revenging the death of his mistress who has been poisoned by the lecherous old Duke; the Duchess' youngest son has been convicted of rape and she herself is trying to seduce the duke's bastard son; the remainder of the court are bent on usurping each other and seizing the crown. Vindice's brother Hippolito meets with him and suggests ways that he might right the wrongs of the past. For the rest of the play, Hippolito is nearly always at his brother's side, advising, chastising and instigating.

Contriving a way to revenge himself, Vindice disguises himself as 'Piato' and enters the service of the Duke's son, Lussurioso. He bids Vindice seduce a young maiden who turns out to be Castiza, his own sister. Horrified at the situation he finds himself in, he nevertheless continues in his disguise, seeing it as a way of testing the virtue of his sister. To his relief, she spurns him. However, their mother Gratiana is far more willing to go along with the seduction, seeing it as a way to advancement at court. The disgusted Vindice smothers his feelings so as to remain in character, but vows to punish his mother's vileness.

Then Vindice finally carries out his long-awaited revenge on the Duke in a scene of unusual ferocity by tricking him into kissing the poisoned skull of his long-dead mistress. The killer unmasks himself so that the Duke recognises Vindice just as he dies. By dressing the corpse in the Piato disguise, he convinces the rest of the court that Piato was the killer, explaining that Piato must have swapped clothes with the Duke before making his escape.

Shortly afterwards the brothers harangue their own mother for her duplicity. She eventually breaks down protesting that only her son's terrifying ability to cajole and persuade had changed her behaviour so. They make up with her, before brutally killing Lussurioso who they find praying. The remaining members of the ruling family end up murdering each other in a finale that sees greed getting the better of everyone. The only exception is the Duchess, who is banished forever.

In the original Vindice survives the bloodbath, but is executed by the Duke's virtuous successor: a revenger, no matter how just his cause, is a man too dangerous to leave alive. However, in Sam Shammas' production, Vindice's dependence on his brother Hippolito brings about a further twist. Hearing Hippolito's final speech in which he holds his brother fully accountable for their arrest and condemnation, Vindice no longer has any reason to live. Seizing his brother's dagger, he mortally wounds himself, dying before justice can be meted out. Hippolito, feeling cheated even by his brother's death, spits at his crumpled corpse as he is dragged away for execution.