Francesco was born in Andria, the son of Guglielmo, second duke of that city, and a daughter of Federico di Brunforte count of Bisceglie.
In 1443 he took part in the first general Parliament of the Kingdom of Naples called by King Alfonso V at Benevento, after its conquest of southern Italy the previous year.
In 1438 the king appointed Francesco as counsellor of the Regio Consiglio ("Royal Council") and sent him as ambassador at the court of emperor Frederick III.
Taking advantage of the duke's absence, a distant relative, Giovanni Antonio Orsini Del Balzo, prince of Taranto, tried to capture Andria, which was defended by Francesco's son Pirro.
After the defeat of Giovanni Antonio and other southern Italian rebels who had sided for John II of Anjou against king Ferdinand, Francesco obtained back all his lands.