The exarchate's origins lie in the final years of the Ottoman Empire, in 1907, when Greek Catholic priest Isaias Papadopoulos was designated vicar general for Greek Catholics living within the Apostolic Delegation of Constantinople. These were Eastern Christians — people who followed the Byzantine Rite and worshipped in Greek — who had entered into full communion with Rome while maintaining their own liturgical and theological traditions distinct from the Latin Catholic Church. The formal exarchate was established on June 11, 1911, initially under the name Greek Catholic Apostolic Exarchate of European Turkey, with its remit covering the Ottoman Empire's European provinces. Papadopoulos was tasked with organizing the new structure, though the appointment of the first actual apostolic exarch had to wait: the Balkan Wars of 1912 to 1913 stripped the empire of most of its European territory almost immediately, and then the First World War disrupted everything further. The first apostolic exarch, George Calavassy, was not appointed until 1920.

In 1932 the exarchate lost territory when a separate Greek Catholic Apostolic Exarchate of Greece was established, with Calavassy himself moving to lead it. The Istanbul jurisdiction was renamed Apostolic Exarchate of Istanbul or of Constantinople in 1936, acknowledging the city's new official name without abandoning the historical resonance of the older one. The exarchate's geographic remit — all of modern Turkey — grew larger in formal terms as borders shifted, even as the community within those borders shrank. It is exempt from normal diocesan hierarchy, meaning it reports directly to the Holy See rather than through any metropolitan bishop. The Greek Byzantine Catholic Church to which it belongs has no metropolitan at all. This structural independence has preserved the exarchate as a distinct entity even through the long decades when it had almost no one left to serve.

The Cathedral of the Holy Trinity in Istanbul is the sole parish of the exarchate. Its liturgical services use the Byzantine Rite conducted in the Greek language — an ancient form of Christian worship that predates the Latin Mass and carries its own distinct chant traditions, ritual gestures, and theological emphases. The community that gathers there now is small and ecumenically layered in ways that would have been unimaginable to the founders of the exarchate: the Chaldean Catholics who hold regular services there are themselves members of a different Eastern Catholic church, displaced from their homelands in the Middle East. Their presence is both a practical necessity and an unintentional testimony to Istanbul's continued role as a place of refuge and convergence for Christian minorities.

Since 1999 the exarchate has been administered by apostolic administrators — churchmen appointed to lead without holding the full title of apostolic exarch. Bishop Louis Pelâtre, a French Assumptionist who also served as Apostolic Vicar of Istanbul for the Latin Catholic community, administered both roles simultaneously from 1999 until his retirement in 2016. Franciscan friar Rubén Tierrablanca Gonzalez followed, then Dominican Lorenzo Piretto, then Massimiliano Palinuro, who continues as administrator. The succession of names from different religious orders and nationalities — French, Mexican, Italian — reflects the Vatican's ongoing care for a jurisdiction that has outlasted the empire that gave rise to it, and that quietly, stubbornly, persists in one of the world's most religiously complex cities.