Archeological excavations that brought to life an italic necropolis in the areas called Porticone and Difesa Grande, next to the Sinarca river, showed that the area was inhabited since very early times, and it seems, from the study of Roman historians, that here rose the center called Interamnia, meaning in Latin between streams, namely the Biferno and the Sinarca rivers. Another etymology derives the name from "thermae", which suggests there might have been Roman spas in the area, which however have not been found so far. With the fall of the Roman empire then most probably the population took refuge on the promontory where today the old Termoli rises, and in Lombard times was included in the Duchy of Benevento, and later on in that of Spoleto.
In the early 13th century the feudal lord was Duke Bartolomeo di Capua, followed by the son of king Robert of Anjou. In the 15th century the fiefdom passed to Carlo di Gambatesa, who was followed by the Di Capua-D'Altavilla family, who kept the title until 1806. For centuries Termoli often attacked by Saracens pirates and by the Venetians.