In the area of ​​the current basilica, Gualtieri VI of Brienne had already founded a monastery in the fourteenth century, but it was only after the mid-sixteenth century that it was decided to transform the area into a monumental area. To find the land, the houses and properties of the Jews were requisitioned, driven out of the city in 1510. Work on the construction of the basilica continued for two centuries, between the 16th and 17th centuries, and involved the most important architects of the time .

The first phase of construction, begun in 1549, ended by 1582 and saw the construction of the lower part of the facade, up to the enormous balcony supported by telamons depicting men and animals. The dome was completed in 1590. According to art historian Vincenzo Cazzato this first phase saw the emergence of Gabriele Riccardi's personality. A subsequent phase of the works, starting from 1606, during which the three decorated portals were added to the facade, is marked by the commitment of Francesco Antonio Zimbalo. Cesare Penna and Giuseppe Zimbalo subsequently worked on completing the work. The first part is due to the construction of the upper part of the facade and the beautiful rose window (near which the date 1646 is carved), to the second one probably the fastigium is attributed to the top of the structure.

The façade is composed of six columns with smooth stems that support the entablature and divide the structure into five areas. The main portal, built in 1606, has pairs of Corinthian columns and displays the insignia of Philip III of Spain, Maria d'Enghien and Gualtieri VI of Brienne. The coats of arms of the Celestine Congregation are displayed on the side doors. The entablature is surmounted by a succession of telamons depicting grotesque figures or fantastic and allegorical animals that support the balustrade, adorned with thirteen cherubs embracing the symbols of temporal power (the crown) and spiritual (the tiara).

The second order of the façade is dominated by the large central rose window of Romanesque inspiration. Profiled from bay leaves and berries, it has three bas-relief orders. The rose window is well highlighted by two Corinthian columns, which separate the central area from the lateral ones in which there are niches with the statues of Saint Benedict and Pope Celestino V. Looking at the rose window, to his left (exactly at nine o'clock), we note the self-portrait of Antonio Zimbalo. At the ends, to close the profile of the second order, stand two large female statues, symbolizing the Faith and the Fortress. The tympanum, with the triumph of the Cross in the center, closes the facade at the top. Following the iconographic program typical of Benedictine spirituality (to which the Celestines belonged) and Augustinian, the façade, as reported by the dedicatory cartouche on the main portal, depicts the triumph of the Banner of the Cross, with allusion, therefore to the exaltation of the sacred wood , whose relic is preserved at the altar of the left transept. The complex figurative system of the telamones that encompasses all cultures and human origins emphasizes the catholicity of the Church and the redeeming power of Christ over the whole humanity.

The Latin cross interior was originally divided into five naves, two of which were later reabsorbed into side chapels added in the 18th century. The vaults of the naves are supported by two orders of columns, in all eighteen, the first two are leaning against the outer wall, the last four paired border the transept and the triumphal arch. The nave is covered by a sumptuous coffered ceiling in walnut with gilding, while the aisles are surmounted by cross vaults. In the intersection of intersection of the two arms of the cross rises a tall dome decorated with festoons of acanthus leaves, little angels and floral motifs. Along the aisles there are seven deep chapels on each side, inside which there are splendid richly decorated altars. Altogether the church receives sixteen baroque altars.