Parts of northern Italy, which were part of the Kingdom of Italy, had been contested by France and the Habsburgs since the end of the 15th century, as it was vital for control of south-west France, an area with a long history of opposition to the central authorities. While Spain remained the dominant power in Lombardy and in Southern Italy, its reliance on long exterior lines of communication was a potential weakness. This applied particularly to the Spanish Road, which allowed them to safely move recruits and supplies from the Kingdom of Naples through Lombardy to their army in Flanders. The French sought to disrupt the Road by attacking the Spanish-held Duchy of Milan or blocking the Alpine passes through alliances with the Grisons.

A subsidiary territory of the Duchy of Mantua was Montferrat and its fortress of Casale Monferrato, whose possession allowed the holder to threaten Milan. Its importance meant when the last duke in the direct line died in December 1627, France and Spain backed rival claimants, resulting in the 1628 to 1631 War of the Mantuan Succession. The French-born Duke of Nevers was backed by France and the Republic of Venice, his rival the Duke of Guastalla by Spain, Ferdinand II, Savoy and Tuscany. This minor conflict had a disproportionate impact on the Thirty Years War, since Pope Urban VIII viewed Habsburg expansion in Italy as a threat to the Papal States. The result was to divide the Catholic church, alienate the Pope from Ferdinand II and make it acceptable for France to employ Protestant allies against him.

After the outbreak of the Franco-Spanish War in 1635, Richelieu supported a renewed offensive by Victor Amadeus against Milan to tie down Spanish resources. These included an unsuccessful attack on Valenza in 1635, plus minor victories at Tornavento and Mombaldone. However, the anti-Habsburg alliance in Northern Italy fell apart when first Charles of Mantua died in September 1637, then Victor Amadeus in October, whose death led to a struggle for control of the Savoyard state between his widow Christine of France and brothers, Thomas and Maurice.

In 1639, their quarrel erupted into open warfare, with France backing Christine and Spain the two brothers, and resulted in the Siege of Turin. One of the most famous military events of the 17th century, at one stage it featured no less than three different armies besieging each other. However, the revolts in Portugal and Catalonia forced the Spanish to cease operations in Italy and the war was settled on terms favourable to Christine and France.