The first documented Jewish presence in Ascoli dates back to 1297, when three Jews from Rome – Angeletto, Musetto and Sabato di Mosè – appeared as part of a consortium of moneylenders along with 19 Christians. They signed a contract with the city council that same year. Jewish ownership of buildings is recorded starting in 1381. Jews appear to have purchased buildings and land in different sections of the city, an indication that they were not required to live in a particular neighborhoods.
The first recorded synagogue dates back to 1515 and was located in the house of Isacco di Mele, in the central district of St. Emidio. In 1550, following the arrival of a large number of Jews from Naples, a second synagogue was established in a building bought by Angelo di Sabato in the Cannettaro district. With the election of Pope Paul IV the Jews of Ascoli were forced into the ghetto which was located in what is today the area between Via Enoc d’Ascoli, Rua David d’Ascoli and Via Giudea.
