With the Spanish domination of the Duchy of Milan, which began in 1535, the Castle was chosen as the seat of the Spanish garrison and was equipped with more modern fortifications and service facilities, necessary to the lives of the soldiers. Around mid-century Sancho de Guevara y Padilla, warden from 1574 to 1580 and governor of Milan from 1580 to 1583, equipped the Castle with a hospital for the troops. A building that backed onto the western curtain wall towards the Vercellina gate was then renovated for this function and was decorated with paintings on the ceilings and walls. The date engraved in Roman numerals MD / LXXVII (1576), still visible today on the shorter wall to the south, probably refers to the completion of the decorative works and coincides with the terrible outbreak in the city referred to as the "plague of San Carlo."

The hospital consisted of a room with three square bays, each illuminated by a window that overlooked the courtyard of arms and another three side-rooms cut into the curtain wall.

Adjacent to the hospital, towards the dead moat, was the apothecary (pharmacy), connected to which were a laboratory, room and workshop. This area, which also included a shed and chicken coop, was the true pharmacy and was connected to the house of the apothecary.

The scarce information available suggests that the hospital was still in operation at the beginning of the 19th century.