"[4] Massinger furnished the first edition with a dedication to Katherine Stanhope (c. 1595–1636), the wife of Philip, Lord Stanhope (then Baron of Shelford and future Earl of Chester), a cousin of Mary Sidney, Countess of Pembroke, and a sister of Henry Hastings, 5th Earl of Huntingdon, who was the primary patron of Massinger's longtime collaborator John Fletcher.
The play is loosely based on historical events in northern Italy c. 1525, during the Italian wars of Francis I of France versus Charles V, Holy Roman Emperor and King of Spain – though Massinger makes no attempt at, and maintains no pretense of, strict historical accuracy.
[7] The Duke of Milan also shows a strong debt to Shakespeare's Othello, for its general plot of a man betrayed by unreasoning jealousy into suspecting his innocent wife and so destroying himself.
Ludovico Sforza, Duke of Venice, is a forceful and formidable ruler, whose "whole life hath been / But one continu'd pilgrimage through dangers, / Affrights, and horrors...." He has one controlling passion – his overwhelming, uxorious obsession with his wife Marcelia.
As one Milanese courtier observes, The duke's mother Isabella and his sister Mariana are especially resentful of Marcelia's dominance at the court; but they have small recourse to remedy their unhappiness.
Sforza goes to confront the Emperor; he behaves with dignity and sincerity, explaining that he maintained his allegiance to the French king out of loyalty for Francis's past support.
In his absence, however, Francisco has made sexual advances to Marcelia; when she rebuffs him, he shows her Sforza's written order for her death.
Sforza rejects the idea; but Francisco, acting on his own motives for revenge, tells the Duke that Marcelia has propositioned him.
His final act in this plan is to disguise himself as a travelling medical man — "A Jew by birth, and a physician" — who can cure the Duke's mental distraction.
In this disguise, Francisco agrees to maintain the fiction that Marcelia is still alive; he paints her corpse with cosmetics, so cunningly that she appears to live again.