The first written documentation regarding Nepezzano dates back to the 12th century in a listing of feudal properties (Rassegna dei Feudatar) found in the county of Teramo (then known as "Aprutina").
The word "Nepotiano" noted on this boundary stone perhaps refers to a Roman colony linked to the larger city of "Pretut" (the ancient name for the town today known as Teramo).
Another small group of country houses, constructed of earth covered straw, was found near Nepezzano in an area today known as Villa Schiavoni.
On 23 June 1809 Nepezzano, along with the neighboring town of Ripattone, suffered greatly when they were captured by Italian brigand troops fighting against the Napoleonic occupation.
For many centuries, the Di Domenicatonio family retained vast holdings of land near Teramo in the suburbs of Nepezzano, Villa Schiavoni, and Coste Sant’Agostino.