The town is very ancient, having been a seat of government of the Vestini people starting around 300 BC. In around 89 BC, the Vestini (along with other Italic tribes) were defeated by the Romans in the Social War, and became citizens of Rome. The town was known as Pinna during the time of the Roman Republic.
In the Middle Ages, Penne was under the control of the Lombards as part of the Duchy of Spoleto. Starting around 1130 Penne became part of the Kingdom of Sicily. In 1538 the town was given by emperor Charles V, Holy Roman Emperor to his daughter Margaret of Parma as a gift for her wedding to Ottavio Farnese. Under Margaret, Penne became important as a center of power in the Abruzzo region, and many fine palaces and civic structures were erected during this time.
Penne's churches include the 12th-century church of Santa Maria in Colleromano, and the Duomo, which now houses the Diocese Museum including a crypt dating from the 8th century. Other churches include Sant'Agostino (with a historical bell-tower), San Giovanni Battista, San Giovanni Evangelista, Annunziata, Madonna del Carmine, San Nicola, San Domenico. The main characteristic of the old town is its streets and houses are built in bricks, so in the past Penne was known as "the small Siena".