Born in Naples, Alfonso was the eldest child of Ferdinand I of Naples by his first wife, Isabella of Clermont. She was the daughter of Tristan, Count of Copertino and Caterina Del Balzo Orsini. Alfonso was the cousin of Ferdinand II of Aragon, king of Aragon and the first (co-)ruler of a unified Spain. His teacher was the humanist Giovanni Pontano, whose De splendore describes the proper virtues and manner of life becoming to a prince.
When his mother Isabella of Clermont died (1465), he succeeded to her feudal claims, which included the Brienne claim to the Kingdom of Jerusalem.
In 1463, when Alfonso was fifteen, his great-uncle Giovanni Antonio del Balzo Orsini, Prince of Taranto, died, and he obtained some lands from the inheritance. Alfonso had shown himself a skilled and determined soldier, helping his father in the suppression of the Conspiracy of the Barons (1485) and in the defence of the Kingdom's territory against the Papal claims.
As a condottiero, he fought in the most important wars of the age, such the war following the Pazzi Conspiracy (1478–1480) and the War of Ferrara (1482–1484).
When his father died, the kingdom's finances were exhausted and the invasion of King Charles VIII of France was imminent; Charles (instigated by Lodovico Sforza, who wished to stir up trouble to allow him to seize power in Milan) had decided to reassert the Angevin claim to Naples and the accompanying title of King of Jerusalem.
Charles invaded Italy in September, 1494. Alfonso managed to regain the support of Pope Alexander VI, who invited Charles to devote his effort against the Turks instead. Alfonso received the official Papal coronation as Rex Siciliae on May 8, 1494 from Juan de Borja Lanzol de Romaní, el mayor, previously the papal legate to Alfonso II.
However, the King of France did not relent; by early 1495 Charles was approaching Naples, after having defeated Florence and the Neapolitan fleet under Alfonso's brother, Frederick of Calabria at Porto Venere. Alfonso, terrified by a series of portents, as well as unusual dreams (perhaps attributable to memories of his victims), abdicated in favour of his son, Ferdinand or Ferrandino, and fled, entering a Sicilian monastery. He died in Messina later that year. It had been 237 days since his coronation.