He was the son of Raimondo Del Balzo Orsini, 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. In 1417 Giovanni Antonio married Pope Martin V's niece Anna Colonna, daughter of the Prince of Amalfi. After James II' renounce, he received the Principality of Taranto from queen Joanna II of Naples on 4 May 1421. This act made him the most powerful baronial lord of the Kingdom of Naples, with lands including 7 archbishoprics, 30 bishoprics, 300 castles an extending from Salerno to Taranto. Giovanni Antonio 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. When Alfonso became king of Naples, Giovanni Antonio further increased his power with the titles of Grand Constable and of Duke of Bari. 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. After several feats of war, Giovanni Antonio and his side were defeated, but in the end, he managed to become reconciled with the Aragonese king. He died in Altamura Castle in 1463, strangled by a certain Paolo Tricarico, perhaps a royal killer. King Ferdinand confiscated most of his lands. His niece Isabella, the legitimate heiress of Giovanni Antonio's lands, died soon afterwards in 1465. Her heir was her eldest son, the futureAlfonso II of Naples.
Illegitimate children
Caterina, Countess of Conversano, Signora di Casamassima e Turi. Married Giuliantonio Acquaviva d’Aragona, 7th Duke of Atri, 1456.
Maria Conquesta, Countess of Ugento, Signora di Nardò e Castro from 1463. Married Angilberto Del Balzo, Count of Tricase and 1st Duke of Nardo circa 1463.
Margherita, married Antonio Centelles, Count of Catanzaro and Justiciar of Calabria.
Francesca, married Jacopo Sanseverino, Count of Saponara.
Bertoldo, Baron of Salice. Some issue. Count of Lecce 1463–64.
Another illegitimate daughter, married Giacomo di Sanseverino, Count of Mileto. Apparently that marriage did not produce any surviving children.