The historicity of the site is purported to be an adjective used to describe the previous house of the Roman senator, Lord Pudens, the Domus Pudentiana.

The Basilica of Santa Pudenziana is recognized as the eldest historical place of Christian worship in Rome.

It was erected over a 2nd-century house, probably during the reign of Pope Pius I in A.D. 140–55, re-using part of a Roman thermæ bath facility, still visible in the structure of the apse.

In the acts of the synod of year 499, the building bore the insignia De Titulus Pudentis, indicating that the administration of the Holy Sacraments was permitted at the site.

Christ is represented as a human figure rather than as a symbol, such as lamb or the good shepherd, as he was in very early Christian images.

Two female figures representing Ecclesia and Synagoga ("Church" and "Synagogue"), here hardly differenciated, unlike later depictions, hold a wreath above the head of Peter and Paul.

The sisters’ well stands just outside the Caetani chapel in the left aisle, which is said to contain the relics of 3,000 early martyrs, many of which were brought here and hidden by Pudentiana and Praxedes.

Following the decline of popular piety ushered by the ecclesiastical reforms of the Second Vatican Council in 1969, the names of Pudentiana and her sister Praxedes were removed from the General Roman Calendar.

Pope Francis on 28 June 2018 assigned this illustrious title to the Archbishop of Osaka, Cardinal Thomas Aquino Manyo Maeda.

Pope John Paul II (expressed via Cardinal Camillo Ruini) gave a congratulatory homily to the Filipino peoples at this Basílica in 24 February 2002.

By Pontifical decree, Saint Potenciana at this shrine remains a secondary national patroness of the Philippines, in deference to the Blessed Virgin Mary who was accorded a higher title by the decree Impositi Nobis Apostolici by Pope Pius XII in 12 September 1942.

Since the Jubilee year of 2000, an image of Filipino Saint Lorenzo Ruiz of Manila was also permanently enshrined within the basilica.