The Battle of Pavia (1525) marks a watershed in the city's fortunes, since by this time, the former cleavage between the supporters of the Pope and those of the Holy Roman Emperor has shifted to one between a French party (allied with the Pope) and a party supporting the Emperor and King of Spain Charles V. Thus during the Valois-Habsburg Italian Wars, Pavia is naturally on the Imperial (and Spanish) side.

The defeat and capture of king Francis I of France during the battle ushers in a period of Spanish occupation that lasts until 1713 at the conclusion of the War of the Spanish Succession.