The work opens by setting the volatile political and social climate of the French Court under Henry the Third, where ambition and corruption dictate the actions of nobility. Bussy D'Ambois, a poor and proud soldier, arrives at Court under the patronage of Monsieur, the King's ambitious brother. His sudden elevation and unapologetic arrogance immediately provoke the enmity of the Duke of Guise and other courtiers, culminating in a ferocious and fatal duel that establishes Bussy's martial prowess.
Following his triumph, Bussy embarks on a dangerous and passionate intrigue with Tamyra, the Countess of Montsurry, aided by a friar who serves as their go-between. This affair fuels the hatred of Monsieur, who discovers the secret and plots with Guise to expose Tamyra's infidelity to her husband. Montsurry, consumed by jealousy, forces his wife to write a deceptive letter luring Bussy into a carefully laid trap.
Despite supernatural warnings from a raised spirit and the ghost of the murdered friar, Bussy falls into the ambush at Montsurry's house. Surrounded by assassins, he fights valiantly before being mortally wounded by a pistol shot. Before his death, he forgives his murderers and urges reconciliation between the grieving Tamyra and her husband.
In the sequel, attention shifts to Clermont D'Ambois, Bussy's philosophical and stoic brother, who resists the unprincipled political machinations of the Court. While visiting Cambray, Clermont is caught in a royal conspiracy orchestrated by his own brother-in-law, Baligny, acting on the King's secret commands. Although briefly captured, his release is secured through the influence of the Duke of Guise.
The narrative builds toward a final reckoning as the ghost of Bussy demands vengeance for his death. Clermont reluctantly executes justice upon Montsurry, but immediately following the deed, news arrives of the assassination of his protector, the Duke of Guise. Weary of the corrupt world and refusing to compromise his principles, Clermont takes his own life in the true Roman fashion.