During the Ottoman era and into the first decades of the Turkish Republic, Ortaköy was a cosmopolitan place with communities of Turks, Greeks, Armenians and Jews.

In the 16th century, the Ottoman Sultan Süleyman the Magnificent encouraged Turks to move to Ortaköy, thereby beginning the Turkish presence in what had been a largely Greek neighbourhood.

One of the oldest buildings in Ortaköy is the hamam (Turkish bath) that was built by the famous Ottoman architect Mimar Sinan in 1556 (this is no longer in use).

During the 19th century the British writer Emilia Hornby rented a house in Ortaköy and left a vivid description of life there in her Constantinople During the Crimean War, published in 1863.

The German architect Bruno Taut lived in a hillside house above Ortaköy that combined Japanese and European architectural styles to reflect his life in exile.

[6] On 1 January 2017, Ortaköy was the scene of a deadly terrorist attack at the Reina nightclub, where hundreds of people were celebrating the New Year.

The exterior of the burnt historic building was left untouched, creating an interesting contrast with its modern interior.