In the 8th century AD a Benedectine monastery rose in the area, and the Lombards built a citadel just above the ancestral settlement. In the 12th century a medieval citadel was flourishing under the name of Greellem. According to one of Abruzzo historian Lodovico Antinori, in the 13th century Guardiagrele was already a land of goldsmiths, and in a manuscript of 1324 prince Ursino gave permission to Luigi Ianuti to establish a corporation of 72 artisans which was called "Schola" from which term probably the frequent surname "Scioli" and its variations may have originated. In the 14th century the town also had its own mint.
It enjoyed great fortune thanks to its boundary location between the territory of the Marrucini with capital Chieti and that of the Frentani with capital Lanciano; Guardiagrele was a market centre where peasants, cattle-breeders and farmers came to sell their produce and to buy tools for their work and homes. Apart from Nicola da Guardiagrele this special town gave birth to many more famous figures, such as poet Modesto Della Porta.