The Italian War of 1542–1546 was a conflict late in the Italian Wars, pitting Francis I of France and Suleiman I of the Ottoman Empire against the Holy Roman Emperor Charles V and Henry VIII of England. The course of the war saw extensive fighting in Italy, France, and the Low Countries, as well as attempted invasions of Spain and England. The conflict was inconclusive and ruinously expensive for the major participants.

The war arose from the failure of the Truce of Nice, which ended the Italian War of 1536–1538, to resolve the long-standing conflict between Charles and Francis—particularly their conflicting claims to the Duchy of Milan. Having found a suitable pretext, Francis once again declared war against his perpetual enemy in 1542. Fighting began at once throughout the Low Countries; the following year saw the Franco-Ottoman alliance's attack on Nice, as well as a series of maneuvers in northern Italy which culminated in the bloody Battle of Ceresole. Charles and Henry then proceeded to invade France, but the long sieges of Boulogne-sur-Mer and Saint-Dizier prevented a decisive offensive against the French.

Charles came to terms with Francis by the Treaty of Crépy in late 1544, but the death of Francis's younger son, the Duke of Orléans—whose proposed marriage to a relative of the Emperor was the foundation of the treaty—made it moot less than a year afterwards. Henry, left alone but unwilling to return Boulogne to the French, continued to fight until 1546, when the Treaty of Ardres finally restored peace between France and England. The deaths of Francis and Henry in early 1547 left the resolution of the Italian Wars to their successors.