The play Duchess of Malfi is named after the character and real life historical tragic figure of Duchess of Malfi who was the regent of the southern Italian town of Amalfi between 1498 and 1510. She was a popular regent, as voiced at the beginning of the play by her lover and, later, husband Antonio:

(Her) days are practised in such noble virtue

That her night, nay more, her very sleep

Are more in heaven than other ladies' shrifts'

While it is debatable whether of not she's the main protagonist—she and her children are killed as early as act 4—it is her decision to marry someone whom her family sees as beneath her that starts the play's tragic chain of events, eventually leading to the deaths of all the play's principle characters.

As her brother Ferdinand states in the final scene, just after the Bosola and the Cardinal have suffered their fatal stab wounds,

My sister, O my sister! there's the cause on't

She is the cause, but through no fault of her own (Webster represents her as a virtuous figure through out). The fault lies with her brothers, the Cardinal, and Ferdinand. The Cardinal wants her to remain an unmarried window so the land of Amalfi remains in the family, and Ferdinand wants her to remain an unmarried widow so he can keep her to himself.

From this perspective, the play's title contains the two things most central to the play's antagonist's atrocious behavior: the land of Amalfi and the Duchess herself.

The play’s full title, The Tragedy of the Duchess of Malfi, presents an interesting conundrum as to what type of tragedy befalls and to whom. Though based upon an actual historical figure and events, some debate whether the play’s tragic focus is truly the Duchess (as the title so easily leads one to believe), when it also could be Bosola’s or something much larger in scope: a depiction of the misfortunes brought about by a corrupt system or world, for instance. Then, one also must consider the nature of the tragedy or revenge play to determine which aspects—personal, social, or political—are weightiest. The themes that Webster incorporated into his drama also provide clues to the title’s scope of influence. Among these are morality, duty, class conflict, deception, marriage, and family.