A hermitage dedicated to St. Onofrio was begun in 1419 by Blessed Nicholas da Forca Palena, who bought the necessary land with the help of alms from the faithful among whom were the Cardinals Gabriele Condulmer (later Pope Eugene IV) and Domenico De Cupis. Around 1439 construction on the church began. Blessed Nicholas and companions joined the discipline of the Congregation of St. Jerome, founded by Blessed Pietro Gambacorti from Pisa in 1446. The church was completed and decorated in the 16th century.
With the motu proprio of August 15, 1945 Pius XII entrusted the church and convent that preserved the memory of the singer of the praises of the Crusaders who fought to regain the liberty of the Holy Sepulcher in Jerusalem, namely the Equestrian Order of the Holy Sepulcher. As time passed the Order lost is monastic and military character and was transformed into a lay organization with the aim of defending and diffusing the faith in Palestine. Today the Knights maintain the Museum of Tasso in the old part of the convent.
In 1946, the Franciscan Friars of the Atonement were invited to administer and maintain the church. This community, founded by Fr. Paul Wattson in 1898 at Graymoor (Garrison, New York), has the mission of praying and working for the unity of Christians. Fr. Paul was an initiator of what became the Week of Prayer for Christian Unity, observed by most Christian Churches and Communities. The Friars in Rome also conduct the Centro Pro Unione in Piazza Navona, an ecumenical center and specialized ecumenical research library.