Don Ferrante Gonzaga, Captain General and lieutenant of the Emperor, initiated large- scale construction on the defences of Milan and the Castle in 1549 in the form of a twelve pointed star or bastion fortification that was at the cutting edge of military architecture. The historic residence of the Sforza family was transformed into a vast garrison containing, according to drawings and literary testimony of the time, a pharmacy, a hospital, shops, a bakery, two bread ovens, a tavern, an ice house - for conserving ice, two churches and vast warehouses. The construction and maintenance of the garrison were paid for by the people of Milan.

The Spanish occupation of the castle is testified to by the armorial bearings painted in 1555 by Don Suarez de Figueroa, the castle manager under Philip II, that are still visible in room II of the Ducal Apartments and by the coats of arms decorating the ceiling of room VII, painted in commemoration of the royal wedding between Philip II and Mary Tudor (1555). The two rooms form part of the Museum of Ancient Art.