Although his pretensions to the throne of France were rejected, Charles Emmanuel benefitted from unrest in that country to seize the marquisate of Saluzzo (1588) and to invade Provence. The new French king Henry IV, however, waged a successful war against him, forcing him to cede three of his dynasty's possessions to the French, though he was allowed to retain Saluzzo. The defeated duke turned his attentions on Geneva but failed in his surprise attack in December 1602.

By the Treaty of Bruzolo (April 1610), Charles Emmanuel aligned himself with the French against the Spanish and Austrian Habsburgs in exchange for a free hand in Lombardy. Although Henry IV's assassination aborted this alliance, Charles Emmanuel seized Monferrato from the Spanish in 1613, provoking a war that lasted until 1617, when he was forced to relinquish the duchy. In the Thirty Years' War, Charles Emmanuel, on the promise of the imperial crown, allied himself with the enemies of the Habsburgs. Yet in December 1627, when he was promised Monferrato, he went over to the Spanish side. After suffering a serious defeat at the hands of the French in March 1629, he died, leaving his state prey to the warring armies.