Francis I became king of France in 1515 and immediately pursued the French claim to Milan. Victory over Swiss forces at Marignano that September restored French control of the duchy and established his military reputation. The Concordat of Bologna in 1516 strengthened the crown's influence over senior church appointments. His unsuccessful bid for the imperial title in 1519 intensified a rivalry with Charles V that dominated much of his reign.

War and diplomacy changed the balance between them. Francis met Henry VIII at the Field of the Cloth of Gold in 1520 but failed to secure a lasting partnership. At Pavia in 1525 his army was defeated and he was captured. His release followed the Treaty of Madrid in 1526, whose territorial concessions he repudiated after returning to France. He subsequently sought allies against Habsburg power, including the Ottoman sultan Suleiman. These arrangements crossed religious divisions.

At home, Francis expanded royal administration and used taxation and officeholding to sustain an expensive court and repeated wars. The Ordinance of Villers-Cotterets in 1539 required French in legal and administrative records in place of Latin. He supported humanist learning through royal lecturers, the institution that developed into the College de France. His religious policy became more repressive toward Protestants, especially after the anti-Mass placards of 1534, despite diplomatic cooperation with Protestant powers abroad.

His patronage transformed royal architecture and artistic production. He brought Leonardo da Vinci to France and commissioned major work at Chambord and Fontainebleau. Italian artists, including Rosso Fiorentino and Primaticcio, helped create a courtly visual language celebrating monarchy. These projects involved large workshops and successive building campaigns rather than the king's design alone. He also sponsored Atlantic exploration, including Jacques Cartier's voyages. Francis died in 1547 and was succeeded by Henry II.