Little is known about this church, its construction dates back to the mid-fourteenth century thanks to some nuns of the order of Sant'Agostino. It is said that two nuns in S. Maria degli Angeli in Murano, Bernarda Dotto and Girolama Lero, set up a convent under the rule of S. Agostino, dedicated to San Girolamo, just outside the walls of Treviso. Shortly after, in 1364, they returned to Venice and retired to a house in San Vitale. Thanks to the generosity of the priest Giovanni Contarini, the convent and church were erected in the current Fondamenta San Girolamo, maintaining the dedication to Saint Jerome. The buildings were enlarged in 1425, twice struck by a fire (1456 and 1705) and both times, the first thanks to the Senate and the second thanks to the charity of the faithful, were arranged. With the reconstruction of the eighteenth century came, the church was rebuilt almost completely on a design by Domenico Rossi.
Only with the Napoleonic edicts of suppression of religious orders, the monastery was converted to private use.
The church stands out not only for its imposing structure, but also for the most important pictorial work inside it depicting San Girolamo by Jacopo Palma the Younger. It is said that, on the sacred day dedicated to San Girolamo, the main magistrates were appointed to replace those who, after their mandate, left office; on that occasion, the doge gave a solemn banquet. It was also considered the day of the beginning of the holidays of the Venetians.