The town's castle was home to a cadet branch of the House of Gonzaga, headed by the Marquis of Castiglione. Saint Aloysius Gonzaga (1568–1591) was born there as heir to the marquisate, but became a Jesuit. 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.
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. There is a museum in the center of the town dedicated to the IRC.