A charming medieval town, with its Estruscan-Roman origins nearly intact, Castelmuzio is named in documents in the 9th century of the Badia Amiatina di San Salvatore, under the name of Casale Mustia. In some texts in the Archives of the State of Siena dating back to 1213, appearing under the name of Castel Mozzo. The people that live there simply call it Castello.
Like the rest of the area, it belonged to the powerful Lords Cacciaconti della Scialenga, whose large domains included from the Fratta farm, not far from Sinalunga, reaching as far as the Castrum of Montepulciano.
In 1270, Castel Mozzo passed to the Republic of Siena and in 1354 the town became property of the Hospice of Santa Maria della Scala in Siena, whose emblem (affixed on a staircase) is still visible in the ornamental decorations put on the facades of some farms in the surrounding areas. For some time, it was ruled by the Salimbeni, then it was acquired by the Piccolomini who owned it until it was reconquered by Siena. With the defeat of the Republic of Siena, Castelmuzio was handed over by the Medici to the Grand Duchy of Tuscany.