The outbreak of World War I in 1914 produced a split in Greek politics, with King Constantine I, an admirer of Germany, calling for neutrality while Prime Minister Eleftherios Venizelos pushed for Greece to join the Allies. The conflict between the monarchists and the Venizelists sometimes resulted in open warfare and became known as the National Schism. In 1917, the Allies forced Constantine to abdicate in favor of his son Alexander and Venizelos returned as premier. At the end of the war, the Great Powers agreed that the Ottoman city of Smyrna (Izmir) and its hinterland, both of which had large Greek populations, be handed over to Greece.

Greek troops occupied Smyrna in 1919, and in 1920 the Treaty of Sèvres was signed by the Ottoman government; the treaty stipulated that in five years time a plebiscite would be held in Smyrna on whether the region would join Greece. However, Turkish nationalists, led by Mustafa Kemal Atatürk, overthrew the Ottoman government and organised a military campaign against the Greek troops, resulting in the Greco-Turkish War (1919–1922). A major Greek offensive ground to a halt in 1921, and by 1922 Greek troops were in retreat. The Turkish forces recaptured Smyrna on 9 September 1922, and setting the city ablaze and killing many Greeks and Armenians.

The war was concluded by the Treaty of Lausanne (1923), according to which there was to be a population exchange between Greece and Turkey on the basis of religion. Over one million Orthodox Christians left Turkey in exchange for 400,000 Muslims from Greece. The events of 1919–1922 are regarded in Greece as a particularly calamitous period of history. Between 1914 and 1923, an estimated 750,000 to 900,000 Greeks died at the hands of the Ottoman Turks, in what many scholars have termed a genocide.