By his father's will he inherited the castle of Livadia and the government of the city of Thebes. He supported Theodore I Palaeologus, Despot of Morea, against the Despot of Epirus, Carlo I Tocco. In 1397, he invaded Attica with expansionist intentions.
In 1400, Venice appointed one of her own, Nicolò Vitturi, podestà in Athens. In 1402, Antonio besieged the city and took it, being proclaimed duke by the populace. In August, Venice offered 8,000 hyperpers for the city and in November Tommaso Mocenigo was sent to offer 1,700 ducats. In January or February 1403, Vitturi finally surrendered the castle and in that latter month, Bernardo Foscarini, the Venetian bailiff of Negroponte was captured in battle. On 31 March 1405, a peace treaty was signed between Antonio and Venice.
Antonio's career was militaristic and adventuresome. In 1406, he took Staria and in 1410 joined the Ottoman Turks to devastate Venetian Nauplia. In 1419, a peace between the Turks and Venice called on Mehmed I to ask Antonio to cease harassing the Venetians. In 1423, he was at war with Theodore II of Morea and occupied Corinth.
Antonio never forgot his Florentine roots and he strove to make Athens a like capital of culture: by renewing the monuments, by patronising letters, and encouraging chivalry. On 7 August 1422, he conceded privileges to Florentine merchants in Athens. In that year, Alfonso V of Aragon asserted his claim by appointing Tommaso Beraldo, a Catalan, duke. Giovanni Acciaioli, Antonio's brother and archbishop of Thebes, who was then in Rome, was sent to Venice to appeal the appointment of Tommaso to the senate there, but the pleas were ignored. Antonio died still in power in January 1435 and left the duchy to his nephews Nerio II and Antonio II under the regency of his widow Matilda Melissene, who never gave him children.