Agnone is in the centre of important archaeological vestiges of the old Oscan-Samnite civilization and has been called "the Athens of the Sannio" due to the large number of ancient ruins of the Samnite culture.

Agnone was an important centre during the rule of the Lombards, but then was left decaying in the centuries immediately preceding 1000, while the Verrino Valley and surrounding hills became a place of hermitages, monasteries and small agricultural colonies.

In 1139 the powerful Borrello family, supported by soldiers of fortune from Venice, probably originating from colonies Dalmatian of the "Serenissima" took control of Agnone.

During this period, the natural resources surrounding Agnone impacted its economy where skilled craftsmen produced gold jewellery, copperware, watches, and bells.

In 1884 the local newspaper L'Aquilonia reviewed the causes of emigration of peasants from Agnone and concluded that the two main factors were excessive taxes on consumers' goods and usurious interest rates that at times surpassed 20 percent in the town.

[8] The peasants were arrested for stealing the crops of the galantuomini ("gallant men" or ruling class), and a particularly frequent crime was the illegal cutting of timber on the town commons.

During the Fascist era, Agnone was the site of exile for many opponents of the ruling party, including Don Raimondo Viale, the protagonist of "The Just Priest" by Nuto Revelli.

The War would finally reach Agnone in December 1943, as the Allied Forces would land on Italy's Adriatic coast and make their way northward and westward to Rome.

The 1st Canadian Infantry Division would drive the Germans and Fascists out of Molise, and on 2 and 3 December, the West Nova Scotia Regiment would billet in Agnone during the Ortona offensive.

Sant'Emidio has a 12th-century portal and rich works of art including wooden painted statues that are taken out on Good Thursday and Friday for a re-enactment of the Last Supper.

[13][14] On Christmas Eve Agnone holds the "Carnevale Agnonese", including the Ndocciata, which is a huge torchlight parade of thousands of handmade, wooden torches made into nine different quarters ("borgate"), accompanied by the sound of bagpipes, to the Piazza Plebiscito where a brotherhood bonfire is lit.

The Fiera delle Arti e Mestieri Antichi (Arts and Antique Crafts Fair) is held from 17 to 19 August where a large area of the old town home to artisans, display their works.