The exact date of construction of the church is unknown. The earliest information about it appears in the geography book of Father Ghugas Inciciyan (1758–1833), which states: “After the Surp Teotoros Mother Church was converted into a mosque in 1515 or 1518, this church was built in its cemetery.” The church also served as a spiritual center of leadership. Its ceiling was made of wood and it contained seven altars. An inscription on the wall records that the church underwent a major restoration in 1722 under the spiritual leader Father Bedros. In those days, the city was home to wealthy Armenians, and the church was adorned with silver and gold liturgical objects, which were later sold during a time of famine.
Between 1610 and 1615, the Polish traveler Simeon described the church in his Travelogue as a magnificent and large building with five altars. Further details are found in Dikran Mguntz’s book Voices from Amid (Amidayi Artzakankner).
The church was completely destroyed by fire on June 10, 1881, but was rebuilt in 1883.
During World War I, it was used as barracks for German officers. The bell tower, built in 1914 at the cost of 2,000 gold coins, was later demolished by locals.
Used for various purposes until 1960, the church was eventually returned to the Armenian community.
When the main church was in ruins, religious services were held in the nearby Surp Hagop Mdzpna Chapel.
After a long and demanding restoration process, the church was reopened for worship in 2011. The restoration was completed through the efforts of the Patriarchal Vicar General, Archbishop Aram Ateşyan, with support from the Municipality of Diyarbakır, as well as generous benefactors from Istanbul and the Armenian community originally from Diyarbakır. The adjacent Surp Hagop Mdzpna Chapel was also restored and re-consecrated in 2012 by Archbishop Aram Ateşyan himself. In the same year, the newly rebuilt bell tower—funded by the benevolence of the Board of Trustees of the Ortaköy Surp Asdvadzadzin Church—was inaugurated.