Born Garegin Hovsepian and originally from Artsakh (then part of the Elizavetpol Governorate of the Russian Empire), he studied at the Gevorgian Seminary of the Catholicosate of All Armenians in Etchmiadzin (1882-1890).
In 1917 he was ordained bishop, Until the outbreak of the First World War, he held a number of teaching and administrative positions within the jurisdiction of the Holy See, in Etchmiadzin, Yerevan, and Tbilisi; he was, at different times, head of the Echdmiazin library, Dean of the Gevorgian Seminary, and editor of the Catholicosate's journal, Ararat.
Following the mass influx of refugees, escaping the Armenian genocide in the Ottoman Empire in 1915-1916, he chaired the Commission of Brotherly Assistance, which looked after the fleeing orphans.
He escaped on 19 January 1921, sought refuge in the city's American orphanage, and, on 21 March, he finally reached Armenian territory, where Soviet rule had already been established.
He played a key role in collecting relief for the victims of the strong earthquake that hit Armenia's second largest city, Leninakan (now, Gyumri) in 1926.
From 1927 to 1933, Karekin was the primate of the Diocese of Crimea and Nor Nakhichevan (a suburb of Rostov-on-Don), which covered Armenian Church parishes and institutions over vast stretches of Russian territory, including Moscow and Leningrad.
A serious schism had arisen in the Armenian Church in North America on the issue of cooperation with the Holy See of Etchmiadzin, which the dissidents complained was fully under Communist control in Soviet Armenia.
Indeed, the locum tenens, Archbishop Gevorg Chorekchian, reported to the National Ecclesiastical Assembly (NEA) in Etchmiadzin in 1941 that the results of Karekin's mission abroad had not covered the financial needs of the Holy See.
Gevorg also asked Karekin to mediate a solution to an administrative dispute within the Armenian Patriarchate in Istanbul, which is traditionally outside the jurisdiction of the Catholicosate of Cilicia.
In 1951, they pushed Gevorg in Etchmiadzin to formally write to Karekin in Lebanon and suggest appointing and ordaining a successor (acceptable to the Soviets) during his own lifetime.
During his reign as Catholicos of Cilicia, Karekin also took tangible steps towards turning the Catholicosate's headquarters in Lebanon into an Armenian cultural center in the diaspora.
In 1951, he published Hishatakarank Dzeragrats (in Armenian Յիշատակարանք Ձեռագրաց), a 1,255 page book about religious and historical references spanning from the 5th century to 1250 A.D.
He was assisted in this project by his Staff-Bearer (gavazanakir), seminary student Torkom Postajian [hy], who traveled to Jerusalem with him and hand-copied and compiled the information from the original documents.