The wide nave survives intact from Justinian's time, although the roof is 15th-century with 19th-century restorations.

Thirty of the nave's 44 columns carry Crusader paintings of saints and the Virgin and Child, although age and lighting conditions make them hard to see.
The columns are made of pink, polished limestone, most of them dating from the original 4th-century Constantinian basilica.

Fragments of high-quality wall mosaics dating from the 1160s decorate both sides of the nave. Each side once had three registers, of which we know the details because of a description made in 1628. The lowest depicted the ancestors of Jesus; the middle contained the decrees of provincial and ecumenical councils; and the top has a series of angels between the windows. The name of the artist, Basilius Pictor, appears at the foot of the third angel from the right on the north wall.

Trap doors in the present floor reveal sections of floor mosaics surviving from the original basilica. The mosaics feature complex geometric designs with birds, flowers and vine patterns, making a rich and elaborate carpet for Constantine's church. Similar doors in the north transept protect another 4th-century mosaic that shows the Constantinian apse was octagonal; these are sometimes opened on request.

The main altar at the east end and the one on the south (Altar of the Circumcision) are the property of the Greek Orthodox Church. The main altar includes an Orthodox iconostasis, which is crowned with gilded angels, icons, gilded chandeliers and lamps. On the north side of the high altar is the Armenian Altar of the Three Kings, dedicated to the Magi who tied up their horses nearby, and in the north apse is an Armenian altar dedicated to the Virgin Mary.