[1] The monastery was built around 1439 on the site of a hermitage[2] founded two decades earlier by Nicola da Forca Palena and is dedicated is to St Onuphrius, a 4th century Egyptian hermit.

The "Salita di Sant'Onofrio", a rather steep driveway to the monastery, was used as a location for the 1958 film Big Deal on Madonna Street.

[3] Behind the Renaissance portico are three lunettes by Domenichino, painted in 1605, commemorating the hermits who lived here and depicting scenes from the life of St Jerome.

The cloister, which is perhaps the oldest part of the complex,[5] has frescoes by the Cavaliere d'Arpino (Giuseppe Cesari) and others depicting scenes from the life of Saint Onuphrius.

[4] Torquato Tasso, the author of Gerusalemme Liberata, the epic poem that retells the deeds of the crusaders who fought to regain possession of the Holy Sepulchre, requested and obtained shelter at the monastery of Sant'Onofrio after wandering all over Italy.