Born in Conversano, Puglia, he was the second son of Duke Giulio Antonio Acquaviva and his wife Caterina Orsini del Balzo.

Upon the death of his father in Otranto, Andrea Matteo, as the elder surviving son, inherited the title of Duke of Atri and Count of S. Flaviano, which made him feudal lord of much of Abruzzo.

Eventually defeated, he was one of the few barons spared, due to the intervention of his father-in-law, Antonio Piccolomini, who happened to be the King's son-in-law.

He was made prisoner by Consalvo of Cordova and carried into Spain; but his confinement was not long; and on his return to Naples he became a patron of letters.

In 1510, Andrea Matteo and other barons assemble in Naples Cathedral to protest the introduction of the Spanish Inquisition into the territory.