The church of Saint Anthony of Padua was built at the end of the 15th century on the remains of a synagogue, in the Jewish quarter of Nardò (The Giudecca). There was a Jewish community living in the town at the time, mainly engaged in leather-working, but it was forced to leave because of anti-Semitic persecution in 1496. The abandoned area of the synagogue was given to the Franciscan Observants, who built the church of St. Anthony of Padua and the adjoining convent (the latter now houses the Museum of Prehistory). The church is located in the old San Paolo district, in the historic centre of Nardò.

The façade was rebuilt in the 18th century and is divided into two orders, in an essential style. The interior is more sumptuous, with a single nave and a fine wooden coffered ceiling.

In the sacristy, the Mausoleum of the Dukes of Acquaviva, is a wonderful sculptural work. A restoration work has recently been completed.