Crete was under constant threat of invasion by Turkey during the last years of Venetian rule. The invasion began in 1645 with the attack on Chania. Sixty thousand Turkish troops landed from a fleet of 400 ships and Chania soon fell. Rethimnon was the next target and in 1646 fell into Turkish hands. By 1648, the Ottoman Empire was in control of Crete, except for Iraklion where the siege lasted twenty-one years. Finally, on 27 September 1669, Iraklion surrendered. The lengthy battle had cost 117,000 Turkish lives and nearly 30,000 lives among the Cretans and Venetians.

Incredibly extensive material destruction followed the conquest: some churches were levelled, others were converted into mosques, and roads and fortifications fell into disrepair.

Many inhabitants fled Crete to escape the persecution of the Ottoman government, while thousands of others became prisoners or fled to the mountains. Large numbers of Turkish settlers arrived and added to the misery of the shrinking Christian population. The Cretans suffered under higher taxes than those in other regions of the Ottoman Empire, farmers became serfs, and private property was seized.

These slave-like conditions led to almost constant uprisings against Turkish control. Daskaloyannis led the first major rebellion in 1770, which was initially successful but was eventually put down by the Turkish forces. Severe reprisals against the Christian population followed this and most other uprisings.

The Greek War of Independence began in 1821 and Cretan participation was extensive. The Turks responded by seeking the aid of the Pasha of Egypt, and brutal campaigns crushed the island's resistance. In 1832 a Greek state was established which, however, did not include Crete and the island passed to the Egyptians, in acknowledgement of their assistance.

Aided by volunteers and reinforcements from free Greece, the "Great Cretan Revolution" began in 1866 and the rebels scored a series of victories. However, as more Turkish forces landed on the island, reprisals, usually against non-combatants, became common. The holocaust at Moni Arkadiou in 1866 became a tragic symbol of Crete's struggle for independence: hundreds of women and children took refuge in the monastery and, refusing to surrender to Turkish forces, blew up the powder magazine, burying themselves and 1,500 Turkish soldiers under the rubble.

Finally, after years of struggle, the Great Powers (Britain, France, Italy and Russia) decided that Turkey could no longer maintain control and intervened with the expulsion of Turkish forces in 1898 which led to the formation of the independent Cretan Republic.