From very ancient times Montelupo was an important crossroads on routes linking the Florence area with the Apennines and the Tyrrhenian coast. Its position and the presence of various watercourses contributed to the development of manufacturing activities, including ceramics, the golden age of which was in the 15th and 16th centuries.This traditional profession lives on today in the many craft workshops dotted around the town and in the Festa Internazionale della Ceramica, which is held in June. During the festival, a series of shows, exhibits and artistic events evoke Montelupo’s history and traditions.
The town probably sprang up when a castle was built here in the early Middle Ages. In 1204, the Florentine Republic conquered the area, rebuilding and expanding the ancient military stronghold.

In the 14th century (1333–36) a new circuit of walls (still visible today) was erected to protect the town that had expanded at the foot of the hill, on top of which is the 13th-century Priory of San Lorenzo.
At the end of the 16th century, the Medici built themselves a large villa on the left-hand bank of the Arno in nearby Ambrogiana. In the last century the villa was turned into a psychiatric facility.