In 1612, Charles, a descendant of the Byzantine Emperor Andronicus II Palaeologus through his grandmother, who was of the line of Theodore I of Montferrat, Andronicus' son. claimed the throne of Constantinople, at the time the capital of the Ottoman Empire. He began plotting with the Maniots of Greece, who addressed him as "King Constantine Palaeologus". When the Ottoman authorities heard about this, they sent an army of 20,000 men and 70 ships to invade Mani. They succeeded in ravaging Mani and imposing taxes on the Maniots. This caused Charles to move more actively for his crusade. He sent envoys to the courts of Europe looking for support. In 1619, he recruited six ships and a number of men, but he was forced to abort the mission because of the beginning of the Thirty Years' War.
At the death of the last legitimate male heir of the Gonzaga line in the Duchy of Mantua, Vincenzo II (1626), Charles inherited the title through an agreement. His son was married with Maria Gonzaga, daughter of former Duke Francesco IV.
However, his succession spurred the enmity of Charles Emmanuel I of Savoy, who aimed at the Gonzaga lands of Montferrat, and, above all, of Spain and the Holy Roman Empire, which did not like a philo-French ruler in Mantua. This led to the War of Mantuan Succession. In 1629 emperor Ferdinand II sent a Landsknecht army to besiege Mantua, Charles left without the promised support from Louis XIII of France. The siege lasted until July, 1630, when the city, already struck by a plague, was brutally sacked. Mantua never recovered from this disaster.
The subsequent diplomatic maneuvers allowed Charles, who had fled to the Papal States, to return to the duchy in 1631, although not without concessions to the House of Savoy and to the Gonzaga of Guastalla. The situation of the Mantuan lands was dramatic, but he was able to trigger some economic recovery in the following years.