The first documentation on the hospital dates from 1309, when, next to the San Lorenzo Cathedral, work began on the construction of the Hospital of St. John the Baptist (whose name was traditionally linked to the Misericordia). When the Misericordia of Siena was suppressed in 1466 the hospital was taken over by the Sienese Santa Maria della Scala, becoming a branch of the latter. In 1591, after the fall of the Republic of Siena, it was used to lodge the soldiers of Grand Duke Ferdinand I de' Medici. It also had a "spezieria", or pharmacy, run by the nearby Franciscan monastery. In 1771, at the initiative of Grand Duke Peter Leopold of Lorraine, the Misericordia Hospital was withdrawn from the administration of the Sienese hospital and put under the authority of the Drainage Office Authority, in keeping with the project for draining the Maremma swamps that also called for the reorganising of medical services. During the first half of the 19th century, the hospital became less important, also because, due to the Maremma land reclamation project implemented by Grand Duke Leopoldo II of Lorraine in 1828, it was no longer receiving the income from the Castiglione Lake that had provided for its financial needs since 1795.