The academic activities of the Pontifical University of the Holy Cross are carried out in the historic Palazzo di Sant'Apollinare, owned by the Holy See and located only a few steps from Piazza Navona within the Ponte (Bridge) district.

The building's present design is the work of the Architect Ferdinand Fuga (1699-1781).

In recent years, a complex restoration has improved the use of available space, allowing the University to accommodate more than 1500 students every year, as well as hundreds of conference attendees coming from more than 70 countries around the world. 

The Research Center, along with the professors' offices and the Library, are located in the complex of buildings situated between Via dei Farnesi, Via Monserrato, and Via di San Girolamo della Carità, within the Regola (Rule) district. In this complex is likewise found the television and radio studios used by the School of Communications.

The University Chaplaincy has its center in the Basilica of Sant'Apollinare, adjacent to Palazzo St. Appolinare, while the Church of San Girolamo della Carità serves as the chapel for the Research Center and the Library.