In the 11th century Pescocostanzo is mentioned in an iscription on a bronze door of the Abbey of Montecassino as "Pescu Costantii cum tredecim cellis et villis suis" (Liborio De Padova, Memorie intorno all'origine e progresso di Pescocostanzo). Prof. De Padova also believes that, since there is no mention of a Lord of Pescocostanzo in the very accurate Catalogum Barorum of 1187, the place was independent until the coming of Angevins, when it came under the Cantelmo family, and later under Nicolò di Sangro. In 1454 it is recorded as partly a possession of Giampaolo Cantelmo duke of Sora and in 1461 belonged to the Caldora family. But the greater part of the territory of Pescocostanzo was a Universitas (a community indipendent from feudal Lords), and the many lords that followed one another always respected the privileges and jurisdiction of this centre.
In the 1500's the lordship was for a long time to Vittoria Colonna, wife and for long decades faithful widow of Ferdinando d'Avalos, Marquis of Pescara. Vittoria Colonna was a poetess and a great friend to Michael Angelo, and it is probably thanks to her influence that the arts began to flourish in Pescocostanzo. The economy was based on cattle and sheep raising since early times, and the wealth derived from the cattle trade favoured the development of crafts and arts. The climate made the inhabitants strong, and this led to a great longevity. There is mention of a Rocco d'Alessandro, living there in 1622, who was 120 years old.
Great names in the history of Pescocostanzo were Davide Coccopalmeri, Archbishop of Malta in the late 15th century, Ottavio Colecchi, a philosopher and mathematician, benedetto Vulpes, a great doctor and scientist.