According to mythology, the first inhabitants of the island of Lefkada were Leleges. The island was named after its most southern part, the cape of Lefkata, with its steep white rocks, from where, according to myth, those who could not endure the torture of love fell, one of them being the great poetess Sappho. In the Middle Bronze Era, the civilization of the island was formed by Televoes, living on the islet of Meganissi. Televoes occupied the Ionian Islands and fought the Mycenaean king. The king's brave nephew defeated them, conquered the islands and offered them to Kefalos from Attica and Hellius from Argolida. Later, Lefkada was occupied by Kefalines, who participated in the Trojan war, under the command of Ulysses. According to myth, Laertis, Ulysses's father, occupied the town of Niriko and offered the island to Icarius, father of Penelope, after her wedding to Ulysses. In spite of the significant alterations of the island's geography and the inadequacy of historical facts, many archaeologists identify the island with Ulysses's Ithaki, mentioned by Homer. Although there are plenty of legendary facts, the historical information from the works of Homer is very significant, a fact corroborated by archaeological excavations. The German historian Dorpfeld supports this theory and situates the palace of Ulysses on the eastern part of the island, in the current position of Nidri.

According to excavations conducted by the German archaeologist Dorfeld at Hirospilia in Evgiros and at Asvospilia in Frini, the first settlements on the island of Lefkada were built during the Neo-Lithic Era (4th millennium BC) and were preserved in the mycenaean years. When the first immigrants from Corinth came to the island, in the 7th century BC, the only city on the island was Nirikos, situated on the current location of Kaligoni, southeast of the island' s capital. After that, the town of Lefkas was built, while, according to testimonies by Stravonas, in 650 BC, the construction of the canal, which separates Lefkada from the mainland, began. Ever since then people have used a bridge 500 feet long and 125 feet wide to get to either side. During this period, the island of Lefkada thrived. After becoming independent, Lefkada remained under Corinthian influence. The island participated in the Persian Wars, sending three ships for the naval battle of Salamina (480 BC), and 800 men for the battle of Plataies (479 BC), while, in 431 BC, Lefkada participated in the Peloponnesian War, supporting Sparta and Corinth. Later, the island of Lefkada sent ships for the expedition against Sicily. The Macedonians conquered the island when the locals supported the Athenians in their battle against the Macedonians, but in 312 BC, Lefkada regained its freedom.

The Romans intervened for the first time in the history of Lefkada, in the 3rd century BC, to sever the island's -union with their rivals, the cities of Akarnanis, which threaten Roman interests. Later, in 230 BC, Lefkada, supported by the Macedonians, resisted a Roman attack. Although the locals fought bravely, Lefkada was conquered by the Roman army of Titus Guintus Flaminius, in 198 BC, after a difficult battle with severe damage, and it became part of the Roman province of Nikopolis. During the Roman Rule, significant physical constructions took place on the island. At the down of the Byzantine Era, Lefkada was part of the province of Achaia. In 325 BC, the island participated in the Ecumenical Convention of Nice, and, 50 years later, a strong earthquake caused severe damage to Lefkada. Due to the island's significant location, a number of powerful states attacked Lefkada, which was destroyed by the Hans and the Vandals, in the 5th century AD. In the next century, Lefkada was included in the "Scheme of Kefalonia", while in 1103 the Pissates attacked the island and caused severe damage. During the Crusaders, the island was part of the Dominion of Epirus.

After the victory of the Franks in Constantinople, in 1204, the island of Lefkada came under their command and, in 1294, it was offered by the Bishop Nikiforos A' Agelos to the Sicilian Orsini family, as a dowry for the wedding of his daughter to Giovanni Orsini. During the rule of the Orsini family, the fortress of Agia Mavra was built to protect Lefkada from the pirates. After a series of several dynasties which ruled the island, Lefkada, from the command of the Andevages and the Tocci, came under Turkish rule.

After several unsuccessful attempts, the Turkish army, led by Gedouk Ahmet Pasha, finally occupied the island of Lefkada in 1479 AD. The Venetians retook the fortress of Agia Mavra in 1502, only to give it back to the Turks through the signing a treaty a year later. Despite the Venetian attacks in 1572 and 1658, the Turkish Occupation lasted until 1684 AD. During this period, the island was constantly attacked by pirates, often because of Turkish indifference or approval, while the locals lived under severe oppression. The most significant piece of construction of the Turkish Occupation was the island's Aqueduct.

In 1684, under the command of Morozini, the Venetians occupied the island of Lefkada and liberated the locals from the Turks. The Venetian Occupation lasted until 1797, while in 1715, for a single year, the Turks managed to regain the island and massacre the locals. In the late 17th century, Venice began its decline and Lefkada came under the command of five consecutive rulers in a period of 13 years (1797 - 1810). The island was initially occupied by the French and Napoleon (1797 - 1800), followed by the Russians (1800 - 1807), when Lefkada was included in the "Ionian State". During the Russian Occupation, Ioannis Kapodistrias the Czar's Minister of Foreign Affairs, managed to prevent the concession of Lefkada to the Turk Ali Pasha. On 8 July 1807, the Treaty of Tilsit again placed the Ionian Islands under Napoleon's french command. In 1810, the English, led by General Oswald, occupied the island and included it in the "United States of the Ionian Islands". The English Occupation ended in 1815, while the status of the English Protection lasted until 1864.

The people of Lefkada offered significant help to the Greek Revolution, in spite of the fact that the island remained under English Occupation. One of Lefkada's most significant personalities was Ioannis Zambelios (1787-1856), who had a significant role in organizing the meeting during which the captains took their solemn oaths, at Panagia Vlaherna, in February, 1821. The common people of the island also helped the cause. After Greece's liberation and the inauguration of the Greek State, in 1830, the English Occupation of the Ionian islands was shaken. In 1864, the Ionian islands, including Lefkada, were united with the rest of Greece. In spite of this fact, the living condition of the people of Lefkada was not improved as a new class, the bourgeoisie, exploited the island's wealth, while the majority of the people lived in poverty. The epidemie of peronspore, in 1900, forced the majority of Lefkada's inhabitants to migrate.

Lefkadio Hearn was born in Lefkada, in 1850. His father was an English army doctor and his mother was Greek from Kythera. He studied in the island and in England and ever since 1869 he worked journalist in the U.S.A. In 1890, he went to Japan where he studied the country and the Japanese culture. His knowledge established him in the scientific circles of Japan and the West. He died in 1904, in Japan. Many, Japanese still come to the island to visit the motherland of this great student.

The great literary man Aggelos Sikelianos was born in Lefkada in 1884. In 1900, he came to Athens to study Law. He didn't complete his studies, because he was too absorbed with poetry. He started writing for Noumas magazine. He believed in the revival of the ancient Greek spirit. The "Delphic Idea" he professed, was the union of the whole of humanity with Delfi as its centre. He dedicated a large part of his life to the revival of the Delphic Festivals. Since 1927, he has organized performances at the ancient theatre of Delfi. He gave two performances there; "Prometheus Bound"(1927) and "Suppliant Women" (1929). During the German occupation, he wrote the tragedies "Sivylla"(1945) and "Christ at Rome" (1946). Other significant works of his include the anthologies of poetry "Lyrical Life", "Moonstruck", "Ionian Rhapsodies" and the tragedy "Thymeli". He was nominated for the Nobel prize for Literature twice. He was married to the rich American archaeologist Eva Palmer, who became his life-long companion. He died in Athens in 1951.

The great Greek poet Aristotelis Valaoritis was born in Lefkada in 1824. His family, active participants in the Greek Revolution, originally came from Valaora in Evritania, or Epirus, while they didn't settle down until Lefkada in the late 17th century -early 18th century. Aristotelis studied in the Ionian Academy and afterwards he studied Law in Paris and Piza, yet he nave worked as a lawyer. In 1852, he married Eloisia Aimiliou Typaldou in Venice and returned to Lefkada. He then pursued poetry and politics. In 1857, he became a congressman of the Radicals in the Ionian Congress while later, after the union of the Ionian Islands with the rest of Greece, he became a representative in the Athenian Parliament. He served as a member of the party of Koumoundouros, until 1869. Aristoteles Valaoritis died in 1879. His work was inspired by his patriotic spirit, country songs and Victor Hugo's romanticism. The mansion of the Valaorits family stands on the islet of Madouri, opposite Nidri.

Ioannis Zambelios, was born in Lefkada in 1787. He studied law in Italy, where he met with great Italian poets and was introduced to poetry. The greatest influence on his work was his meeting with Adamandios Korais in Paris, in 1810. During the Greek Revolution, Zambelios became part of the Hetaeria and helped the Greek Cause significantly. He is said to have organized the melting and inauguration of his life working as a judge in Corfu, where he died in 1856. He wrote dramas with historical and patriotic themes. The first one was "Timoleon" (1818), followed by "Constantinos Palaiologos", "Regas Thessalos", "Markos Botsareis" and "Medea".