Later followed the First War of Castro, in which Francesco's Modena joined Venice and Florence and sided with the Dukes of Parma against Barberini Pope Urban VIII, aiming to reconquer Ferrara.

When he however failed to conquer Cremona, and as the situation of the Thirty Years' War seemed to be favourable for Spain, the Duke sought for an agreement with the latter.

He returned to the service of France by marrying his son and heir Alfonso to Laura Martinozzi, Mazarin's niece.

After successful resistance to a Spanish invasion from their territories in Milan, he fought alongside France and Savoy, conquering Alessandria and Valenza in 1656–1657 with the help of his son.

Much of the freedom and spontaneity of the bust of Cardinal Scipione Borghese is kept, but it is united with a heroic pomp and grandiose movement that portray the ideals of the Baroque age as much as the man.