In 1628, the death of Vincenzo II Gonzaga, Duke of Mantua, without heirs, sparked not only a dynastic dispute but a war between great powers. France and the Habsburg Empire were poised to intervene to control one of the most strategic territories of the Italian peninsula. Following his death, Vincenzo II's closest candidate was Charles of Gonzaga-Nevers, a French branch of the family. But precisely this connection to France made his succession unacceptable to the Empire, which feared the expansion of French influence in Italy.

In 1629, imperial troops descended on Italy. The Duchy of Mantua and Monferrato, the Piedmontese fiefdom of the Gonzagas, became the centre of the conflict. The city of Mantua, one of the most refined courts in Europe, was prepared for siege. In 1630, imperial troops laid siege to Mantua. The city resisted, but when the imperial troops entered, it was sacked, with violence, destruction, and the loss of works of art. A city that was a symbol of the Renaissance was brutally attacked. Furthermore, the plague, spread by invading armies, hit Northern Italy hard. The combination of war and epidemic transformed the conflict into an even larger tragedy, leaving territories depopulated and cities in ruins. Meanwhile, France intervened to support Charles of Gonzaga-Nevers. The local war thus became part of the Thirty Years' War, becoming one of the many fronts of a great European conflict.

Eventually, in 1631, the Peace of Cherasco was reached. Charles of Gonzaga-Nevers obtained the Duchy of Mantua and Montferrat, while some concessions were made to the Empire. Charles Emmanuel I of Savoy, who aspired to seize Monferrato and intervened in the conflict, first on the side of the Empire and then on the side of France, obtained some territories of the Piedmontese fiefdom. The issue was resolved, but Mantua was no longer the same. What had been one of Italy's cultural capitals emerged from the war marked by devastating loss. A splendid court had become a symbol of decline. This war had also demonstrated that in European politics of the time, no crisis was truly local.