Henry II became king of France in 1547, continuing the Valois struggle against Habsburg power while strengthening royal government at home. His court relied on networks associated with Anne de Montmorency and the Guise family. His wife Catherine de' Medici supplied the dynasty's heirs, while his favorite Diane de Poitiers exercised substantial influence and received extensive patronage.

Henry pursued war against Emperor Charles V while supporting German Protestant princes for strategic purposes. Under the agreement at Chambord in 1552, French forces occupied Metz, Toul, and Verdun. The Duke of Guise successfully defended Metz against the emperor's subsequent siege. These gains strengthened France's northeastern position, although possession and legal recognition were separate matters. Italian campaigns also consumed money and troops.

After renewed war with the Habsburgs and their English allies, French forces suffered a major defeat at Saint-Quentin in 1557. The capture of Calais by Guise in January 1558 provided a dramatic counterweight, ending more than two centuries of English possession. The treaties of Cateau-Cambrésis in 1559 closed the Italian Wars: Henry abandoned major French claims in Italy while retaining important northern and eastern gains. Dynastic marriages helped seal the peace.

At home, Henry persecuted Protestantism despite his alliances with Protestant rulers abroad. Specialized judicial proceedings and increasingly severe edicts sought to suppress religious dissent, but French Reformed churches continued to organize and attract noble supporters. His reign therefore ended without resolving the tensions that would soon produce civil war. During festivities marking the peace, he was gravely injured in a tournament against Gabriel de Montgomery in June 1559 and died in July. The accession of his young son Francis II exposed the monarchy to intensified factional competition, amid lasting financial and religious tensions.