Throughout the 9th century the area was repeatedly sacked during Muslim invasions and suffered an earthquake in 847; these destroyed the cities of Isernia and Venafro.

A 1979 archaeological discovery near the city of Isernia found evidence of a settlement dating back to the Palaeolithic period over 736,000 years ago.

[5] In Molise County, Benedictines formed the San Vincenzo al Volturno monastery in the province of Isernia after Rome fell in 476.

When the area was invaded by the Muslims, 500 to 900 monks were decapitated by them and many were taken as slaves; despite this, the monastery continued to function and reached its peak size during the eleventh and twelfth centuries.

Traditional products grown in the province include grass peas (Lathyrus sativus) and farro, which is made from a specialist form of wheat.