The area of modern Acquapendente was settled by Etruscans and Roman times, as findings have showed. However, the first historical document of the modern city date from the 9th century AD, with a burg named Farisa or Arisa along the Via Francigena. In 964 a document of Emperor Otto I contains for the first time the name Acquapendentem. The name of the city, meaning "Pending Water", stems from the presence of several small waterfalls forming the Paglia, a stream setting the boundary between Lazio and Tuscany.
The city was later part of the Mark of Tuscany and, from the end of the 14th century and beginning of the 15th, it was part of the commune of Siena. In 1449 it become an independent centre within the Papal States.
Acquapendente was also the birthplace of the anatomist Hieronymus Fabricius.
