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Since prehistory there was a settlement in this fertile plain created by the Tammaro River where the local population traded with migrating shepherds. In the Iron Age a citadel of Samnites supervised over this trading activity: the citadel, surrounded by mighty walls, was called Saepins, and ruins can still be seen on the top of a hill called Terravecchia (953 mt above sea level).
During the second Samnite War in 293 b.C. Saepins, "fortissima atcque potentissima" was conquered by consul Lucius Papirius Cursor. The heroic Samnites went out of the town to fight the Romans, and 7300 of them died, while 3000 were taken prisoners(as reported by historian Livius). The few who survived abandoned the citadel and settled in the plain, where later the new Roman town of Saepinum was to rise.
The Roman town flourished during the imperial period. Recent excavations still in progress have brought to light the remains of private buildings, a fairly large theatre, a basilica, the forum, the "Griffon Fountain", two mausoleums, baths, and long stretches of boundary walls with four gates.
In the 1st century AD Saepinum was one of the 35 Roman municipia in Italy, and economic development started under Augustus who granted of parcels of land throughout Italy to veterans returning from foreign wars, and also Saepinum saw new landowners just outside the city-walls. At that time it was also surrounded by walls and greatly flourished under Tiberius and his brother Drusus. The Neratia family had their origin here, and a member, Neratius Priscus, was a celebrated law scholar under Traianus.
In the 5th century it also became a bishopry, then after the Lombard invasions took the name of Altilia and in 668 AD was given with Isernia and Boiano to Alczeco, a Bulgarian Duke. In the 9th century was raided by the Saracens, and at that time the inhabitants moved to a higher position, where the present Sepino is still situated.