He followed his grandfather Charles I, Duke of Mantua, in 1637 as ruler of these lands, the first ten years under regency of his mother Duchess Maria.

On 22 March 1657, Charles II receives the appointment as Imperial Vicar in Italy.

The marriage was an act of diplomacy and they had only one child, his successor Ferdinand Charles, Duke of Mantua and Montferrat (1652–1708).

[3] In his book, The Last Medici, Harold Acton records that his death occurred in the midst of lascivious intercourse.

In 1657, he appointed the Flemish painter and printmaker Daniel van den Dyck as his official court painter, architect, surveyor of his building program and engineer for stage designs for the theatre.