The brother of Mehmed V Reşâd, he became heir to the throne in 1916, after the death of Şehzade Yusuf Izzeddin, as the eldest male member of the House of Osman.

Mehmed VI's reign began with the Ottoman Empire suffering defeat by the Allied Powers with the conclusion of World War I.

The subsequent Armistice of Mudros legitimized further Allied incursions into Ottoman territory, resulting in an informal occupation of Istanbul and other parts of the empire.

During the Paris Peace Conference, Mehmed VI turned to Damat Ferid Pasha to diplomatically outflank Greek territorial demands on the Ottoman Empire through Allied appeasement, but to no avail.

Mehmed's most significant act as Sultan was dispatching Mustafa Kemal Pasha (Atatürk) to reassert government control in Anatolia, which actually resulted in the further consolidation of anti-appeasement actors against the court, and consequently, the end of the monarchy.

Mehmed VI condemned the nationalist leaders as infidels and called for their execution, though the provisional government in Ankara claimed it was rescuing the Sultan-Caliph from manipulative foreigners and ministers.

On 1 November 1922, the Grand National Assembly voted to abolish the Sultanate and to depose Mehmed VI as Caliph, and he left for Europe in exile.

When he ascended to the throne, this closeness greatly influenced his political attitudes, such as his intense dislike of the Young Turks and the Committee of Union and Progress (CUP), and his sympathy for the British.

A new government, consisting of members of the Liberty and Accord Party, arrested the leaders of the CUP, including one of the former grand viziers, Said Halim Pasha.

On 22 July 1920, the Sultanic Council (Şurayı Saltanat) gathered in Yıldız Palace to discuss the principles of the settlement debated in Sèvres.

A new government, the Turkish Grand National Assembly, under the leadership of Mustafa Kemal Pasha, was formed on 23 April 1920, in Ankara (then known as Angora).

The new government denounced the rule of Mehmed VI and the command of Süleyman Şefik Pasha, who was in charge of the army commissioned to fight against the Turkish National Movement (the Kuvâ-i İnzibâtiyye); as a result, a temporary constitution was drafted for Kemal's counter-government in Ankara.

As the nationalist movement strengthened its military positions in late August 1922, Mehmed VI, his five wives, and attendant eunuchs could no longer leave the safety of the palace.

[19] Leaving aboard the British warship HMS Malaya on 17 November 1922, he took care not to bring valuable items or jewellery, other than his personal belongings.

Accompanied by his First Chamberlain, the bandmaster, his doctor, two confidential secretaries, a valet, a barber and two eunuchs, at 6 am on 19 November, two British ambulances took them to the house of General Sir Charles Harington.

[20] His daughter Sabiha Sultan found money for a burial, and the coffin was taken to Syria and buried in the cemetery of the Sulaymaniyya Takiyya in Damascus.

The sources in question also state that he was intelligent and quick-grasped, but he was under the influence of his entourage and especially those he believed in, that he had a very evident, unstable and stubborn temperament.