The Cathedral is built on the highest point of the Borgo Vecchio, in the place of the oldest urban settlement, as evidenced by some archaeological finds dating back to the Bronze Age. 
The first building stands, probably on the ruins of an ancient pagan building of which there are no traces. Over the centuries the Cathedral suffered natural calamities and looting that devastated it considerably. 
Towards the middle of the 18th century, floor mosaics and the remains of apses of the pre-existing religious building came to light.
With the recent restoration interventions, other parts of the floor mosaic came to light and a large cemetery area under the premises of the sacristy, dating back to the 9th century in the oldest layers. On 31 December 1761 the bones of S. Basso, patron saint of Termoli, were found in the crypt of the Cathedral; while, in May 1945, those of St. Timoteo, the disciple of St. Paul, were found.