The first inhabitants of Panicale were the Indo-European tribe, the Aequi, in the 14th Century BC. The pastoral tribe, the Italics, then created the first town. Afterwards, the Etruscans made Panicale an important agricultural center. Finally, the Romans were whose fortress made Panicale into its current shape.

Panicale used to have seven churches and 12 priests in town. Nowadays, there is one priest and three churches still in use, while the others are mainly museums.