The site has been a place of Christian worship since at least the 6th century, when a Byzantine-rite abbey is documented on the northern summit of the Capitoline Hill in 574. Passed to papal control by the 9th century and then to the Benedictines, the church was transferred in 1249–1250 to the Franciscan Order, which rebuilt it into the Romanesque-Gothic basilica visible today. In 1348 the Roman people commissioned the Cordonata — a monumental flight of 124 marble steps designed by Lorenzo di Simone Andreotti and traditionally said to be an ex-voto for the end of the Black Death. The staircase was inaugurated by the tribune Cola di Rienzo, who used the basilica as a stage for the civic and religious life of the late-medieval city.

The interior is divided into a nave and two aisles by twenty-two antique columns, each spoliated from a different Roman monument, and paved with a Cosmatesque floor. Halfway down the right aisle, the Bufalini Chapel preserves Pinturicchio’s fresco cycle of 1486 on the life of Saint Bernardino of Siena — one of the earliest fully Renaissance fresco programmes in Rome and a key work for understanding the Umbrian master before his Borgia Apartments. Above, the coffered gilded ceiling, completed around 1575, was commissioned by the Roman Senate and the Conventual Franciscans to commemorate the victory of the Holy League over the Ottoman fleet at the Battle of Lepanto on 7 October 1571. In a chapel off the left transept stood the Santo Bambino, a 15th-century figure of the Christ Child carved from olive wood reputed to have come from the Garden of Gethsemane, taken in procession to the bedsides of the sick.

On the night of 1 February 1994 the original Santo Bambino was stolen from the basilica and has never been recovered; the figure now venerated in the dedicated chapel is a faithful copy, again carved from olive wood from Gethsemane. The basilica remains an active Conventual Franciscan church and the titular seat of a Cardinal-Priest, but it also retains its civic role as the designated church of the city government of Rome under the ancient title Senatus Populusque Romanus — the Senate and People of Rome — used for solemn celebrations involving the Capitoline authorities. Access is free; the climb up the Cordonata, from Piazza d’Aracoeli, is part of the experience the church has offered the city since the fourteenth century.