The Paulist Fathers' ministry to United States Catholics subsequently moved to San Patrizio (Saint Patrick).

A vast mosaic of Christ flanked by Leo and the Emperor Charlemagne, and Saints Susanna and Felicity on the other side, was so badly damaged in the 12th century by an earthquake that the interior was plastered over in the complete renovation that spanned the years 1585–1602, and frescoed by Cesare Nebbia.

The church of Santa Susanna was accounted so successful that in 1605 Pope Paul V named Maderno architect of Saint Peter's Basilica, where he completed the nave and constructed the great façade.

One of the objectives pursued with greater commitment from Rusticucci as the vicar general of Pope Sixtus V was to renew the life of the religious orders.

Rusticucci wanted to highlight and connect these themes to the inseparable bond that his church had with the Cistercian nuns whose monastery occupied the site.

To Cesare Nebbia, a native of Orvieto (1536–1614), can be attributed the frescoes in the dome and apse curve in which are reproduced some scenes from the life of Susanna.

Camilla Peretti, sister of Pope Sixtus, was a great benefactor of the Cistercian nuns, and helped build their residential quarters, including the Chapel of St Lawrence whose frescoes are the work of Giovan Battista Pozzo (1563–1591).

Large statues of the major prophets and two of Peter and Paul are attributed to Giovanni Antonio Paracea, called Valsoldo.

Through the glass floor of the sacristy can be seen part of the early Christian Church and the remains of the Roman house, which is said to be the home of the father of Susanna.

Also in the choir, in the four branches of the two niches that preserve the reliquaries, appear Benedict of Nurcia and Scholastica (left) and Bernard of Clairvaux and Susanna (on the right), all by the Umbrian painter Avanzino Nucci (1599).

The frescoes of the central nave by Baldassare Croce represent six scenes from the life of Susanna found in the Book of Daniel.

Domenico Fontana constructed the second side-chapel to the left, dedicated to Saint Lawrence and commissioned by Camilla Peretti, sister of Pope Sixtus V. The paintings are by the Milanese artist Giovanni Battista Pozzo (1563–1591).

The valuable ceiling of the nave and of the presbytery is made in polychromed gilt wood, carved to the design of Carlo Maderno.

After World War I, the Paulist Fathers, founded in New York City in 1858, had grown to such an extent that they felt the time had come to seek approval of their religious institute from the Holy See, in order to be able to work throughout the worldwide Catholic Church.

Cardinal William Henry O'Connell of Boston presided at the first public Mass for the American community of the city on 26 February 1922.

The ownership issue settled at the end of 1924, when Bonzano, the former Apostolic Nuncio and by then a cardinal himself, requested a transfer of his title to this church.

Bernard Francis Law remained the titular cardinal until his December 2017 death, though he resigned as archbishop in 2002 in the wake of the sexual abuse scandal in his archdiocese.

Since August 2017, following a campaign by the Cistercian nuns who had maintained a presence at Santa Susanna since 1587, the American expatriate community relocated its national church to San Patrizio.