[1] The first castle was probably erected at this location around 1300 by John I Orsini, the Count palatine of Cephalonia and Zakynthos, who received possession of Lefkada (then known as Santa Maura) in 1295 from his father-in-law, the Despot of Epirus Nikephoros I Komnenos Doukas.

[1] The Orsini family lost Lefkada in 1331 to Walter VI of Brienne, who in 1343 ceded the castrum Sancte Maure and the island to the Venetian Graziano Giorgio.

[5][6] Carlo I Tocco (r. 1376–1429) made the castle the capital of his domains, which apart from the County palatine of Cephalonia and Zakynthos also included much of the Epirote mainland, and enlarged the fortified town.

[7] In 1413, the Prince of Achaea, Centurione II Zaccaria, launched an attack on Lefkada and its castle with Albanian mercenaries, but it was defeated with help from the Republic of Venice.

[1][10] Under Ottoman rule, the town inside the castle (known as Aya Mavra, ايامورة, from Greek Αγία Μαύρα) was the capital of the island.

[9] By the time Evliya Çelebi visited the castle in 1670/71, only Muslims lived in its c. 200 stone houses, with the Christians in two adjoining suburbs to the east and west and one on the island itself.

[14] During the Seventh Ottoman–Venetian War, following the rapid Ottoman reconquest of the Morea in 1715, the Venetians initially abandoned Lefkada to focus their resources on the defence of Corfu.

[14] Following the Fall of the Republic of Venice in 1797, Lefkada, like the other Venetian Ionian Islands, was occupied by the French, who held it until a Russo-Turkish expedition under Ushakov captured it in 1799.

[17] Ali Pasha of Ioannina, who coveted possession of the Ionian Islands, besieged Lefkada in 1807, but the local Russian and Greek forces of the Septinsular Republic successfully defended the fortress.