Cephalonia had not always been contested ground. Before 1479 the island was held by the Italian counts palatine of the Tocco family, who had governed these Ionian waters since the Frankish era. The First Ottoman–Venetian War ended that arrangement. Ottoman forces captured Cephalonia in 1479, and with the exception of a brief Venetian recovery in 1482–83, the island and its ancient hilltop fortress remained in Ottoman hands for the next two decades. For the Venetians, Cephalonia was a strategic loss they could not afford to ignore: the island sat astride the sea lanes that connected Venice to its colonies in the eastern Mediterranean. Losing it meant losing control of some of the most valuable shipping routes in the world.

When the Second Ottoman–Venetian War broke out in 1499, it went badly for Venice from the start. Lepanto — the great port on the Greek mainland that controlled access to the Gulf of Corinth — surrendered to the Ottomans on 24 August 1499. Then, in the summer of 1500, the Ottomans stormed Modon on 9 August, one of Venice's most important fortified harbours on the Peloponnese coast, and the neighbouring forts of Coron and Navarino surrendered soon after. The Ottoman advance seemed unstoppable. Venice, stretched thin across its maritime empire, was running out of options.

The reversal began on 17 August 1500, when Gonzalo Fernández de Córdoba — the Spanish general known across Europe as El Gran Capitán, the Great Captain — offered his forces to Venice's aid. His was not a casual gesture. Córdoba had already transformed European warfare with his innovations in infantry tactics during the Italian Wars, and his willingness to commit Spanish sea power to the Venetian cause changed the balance in the Ionian theater. Together with the newly appointed Venetian captain-general of the Sea, Benedetto Pesaro, Córdoba landed his combined force on Cephalonia in November 1500. What followed was a siege of nearly seven weeks, methodical and grinding, until the castle's defenders could hold no longer.

The Castle of Saint George fell on 24 December 1500. Córdoba's fleet then returned to Sicily, its obligation to Venice fulfilled. Pesaro pressed on, and in August 1502 he recovered Santa Maura — the island Venice knew as Lefkada — from the Ottomans as well. But the peace treaty concluded in Constantinople in December 1502 drew a complicated line: Cephalonia remained in Venetian hands, a permanent gain, while Lefkada was returned to Ottoman rule in 1503. The siege had saved the island, but it had not ended the contest for the broader Ionian world. Venice would continue to fight Ottoman expansion for another two centuries before the Republic itself finally fell.

The Castle of Saint George still stands on its hill above the village of Peratata, roughly eight kilometres south of Argostoli. The walls that Venetian and Spanish soldiers breached on Christmas Eve 1500 are still largely intact, and the fortress remained Cephalonia's capital until the Venetians relocated their administration to Argostoli in 1757. Visitors can walk the ramparts and look out over the same Ionian panorama — the flat plain of the Livathos below, the sea to the south, and on clear days the outline of Zakynthos to the southeast — that soldiers and besieged garrison alike would have surveyed in the final weeks of that long, remarkable siege.