The town's castle was home to a cadet branch of the House of Gonzaga, headed by the Marquis of Castiglione.

He died tending plague victims in Rome and was buried there, but his head was later translated to the basilica in Castiglione which bears his name.

During the War of the Spanish Succession, the French under the duc de Vendôme occupied the town.

During the siege of Mantua in 1796, the Austrians under Dagobert Sigmund von Wurmser were defeated here in the second Battle of Castiglione by the revolutionary French army under General Augereau, later Marshal of France, who in 1808 was created Duke of Castiglione by Emperor Napoleon I, a hereditary victory title (so there never was an actual territorial duchy attached to it) extinguished in 1915.

Castiglione is the birthplace of the International Red Cross, which was established by Henri Dunant during the aftermath of the Battle of Solferino in 1859.