San Casciano's territory was inhabited since Etruscan times, as evidenced by archaeological findings in Montefiridolfi (The Bowman's Grave) and Valigondoli (Poggio La Croce's excavations).

There is little doubt that the area was still densely populated in the Middle Ages, based upon the many castles which were built at the time for the bishopric of Florence or powerful families like the Buondelmonti or Cavalcanti.

By 1325 San Casciano had become so important that a statute of the Florence podestà described one of the main roads departing from the city as follows: "strada per quam itur ad ‘"Sanctum Cassianum"’ (…) versus civitatem Senarum et versus romanam Curiam" (i.e. "the road going through San Casciano towards Siena and Rome”).

That San Casciano's history is bound to its roads is shown also by its shape, which is in the form of a cross: one side going from Florence to Siena and the other, following the hills' ridge, linking the Chianti area with Montelupo and the Arno river basin.

San Casciano was occupied by the Holy Roman Emperor Henry VII from November 1312 to January 1313, the Duke of Lucca Castruccio Castracani in February 1325, and the French mercenary Moriale D'Albarno in July 1343.

In 1893, after the annexation of the Grand Duchy of Tuscany to the Kingdom of Italy, a steam-engine railroad was built to link San Casciano and Florence.