Near the outskirts of Isernia were discovered the first traces of human civilization in the territory of Molise, dating back as far as 730,000 years.
The region, originally called Sannio, was inhabited by the Sannitiin fact. They came to this region, according to Strabone, in the 6th century B.C. . It was because of the continuous battles between the Sabini and the Umbri, that brought immigrants, for their survival, to establish themselves on the hill they called Sannio, and to found the town of Boiano in honor of their sacred bull.

The Romans fought against the Sanniti (between 343 and 293 A.D.) to gain control over the territories they occupied. These wars are remembered for their violence and bloodiness
In the 1st century B.C., after the war, town councils were established by the Romans. Other than the town of Boiano (originally called Bovianum), other important centres were built such as Terventum, Saepinum, Fagifulae (near Montagano).

Molise, after the fall of the Western Roman Empire (5th century B.C.), was overcome, as were the other Italian regions, by the violent invasions of the Visigoths, Eruli, Vandals and Ostrogoths. These tribes destroyed almost everything, especially farming, the main resource of the region’s inhabitants.
Under the Longobards, though , the region was reconstructed , life near the castles was reborn, while the Benedictine order started to improve the lands for agriculture and build convents and abbeys (one of the most renown is the one of San Vincenzo sul Volturno.

Starting from the first half of the 11th century, the Normans conquered the region, which was already very weak following incursions by the Saracens in the previous centuries. It was King Federico II who re-established unity and peace between the various factions, and created the Norman-Swede Kindom. The region, then, was dominated by the French with the Angiò family, who was replaced, in 1442, by the Alfonso family, who had their kingdom over Aragona and Sicily.

Molise, from this point in history on, followed the outcome of the rest of southern Italy, which remained under Spanish influence until the Italian Risorgimento. In the autumn of 1860 and after the intervention of Garibaldi with his Piedmont troops, the region of Molise, was annexed to the new born Reign of Italy, under the sovereignty of Vittorio Emanuele of Savoia.