Born in Lecce, he was the son of Raimondo Orsini del Balzo, Prince of Taranto, and Mary of Enghien, an heiress of the Brienne main branch.

When his father died, he was one year old, and his mother married with King Ladislaus of Naples, who acquired all the family's possessions (1407).

This act made him the most powerful baronial lord of the Kingdom of Naples, with lands including 7 archbishoprics, 30 bishoprics, 300 castles and extending from Salerno to Taranto.

Giannantonio was also an influent member of the Neapolitan court, and remained engulfed in the struggle between Joanna and Alfonso V of Aragon, whom he supported in the civil war against John II of Anjou.

However, when Alfonso died, he retreated to Taranto to head a group of barons against the former's son, Ferdinand I, in favour of John II.