In mediaeval times a substantial number of pilgrims from Wessex, including fighting men, traveled the Via Francigena from Canterbury to Rome.

In 1538–1545, Antonio da Sangallo the Younger, or Baldassare Peruzzi, rebuilt the church after it had been damaged during the Sack of Rome.

In 1585–1590, Pope Sixtus V had the exterior restored, giving the church its present façade by Ottavio Mascherino, inspired by a design of Sangallo.

In the upper middle section is a circular window, and above that is the coat-of-arms of Pope Sixtus V. The façade is crowned by a pediment.

In the stational procession for the first Sunday after the Octave of the Epiphany, instituted by Pope Innocent III (1198–1216), a procession carried the veil of Saint Veronica from Saint Peter's Basilica, and the Pope celebrated Mass in this church.

The inscriptions found in Santo Spirito in Sassia, a valuable source illustrating the history of the church, have been collected and published by Vincenzo Forcella.