
A few months after being ordained deacon in 1901, he took the vow of celibacy and was ordained vartabed in 1902. In between, he had been designated reformer of the churches of the region of Nor Bayazet (now Gavar). In June 1903, he resisted the confiscation of the properties of the Armenian Church by the Russian government and was arrested and exiled to Orel, Russia.
He returned from exile in 1905 and was named diocesan vicar of Gori-Imereti-Batum and Ardvin. A patriarchal encyclical by Catholicos Megerdich I Khrimian designated him reformer of the churches of Nor Bayazed and Darachicak (now Tsaghkadzor).
He was elevated to bishop in December 1909. He served as the president of the Committee of Brotherly Aid during the years of World War I, and organized assistance for wounded Armenian soldiers and refugees.
Bishop Khoren Muradbekian took the initiative of founding the Armenian National Council in Yerevan in 1917. By arrangement of Catholicos Kevork V Sureniants and order of the government of the Republic of Armenia, he went to Paris in 1919 as the Patriarchal Legate to settle the differences between the two Armenian delegations that participated in the Peace Conference (Delegation of the Republic of Armenia, led by Avetis Aharonian, and Armenian National Delegation, headed by Boghos Nubar).
In 1920 he traveled from Paris to the United States to resolve the discord in the diocese of America. He organized a fundraiser for the defense and reconstruction of the Republic of Armenia, and arranged for diocesan elections. In 1921, Archbishop Tirayr Der Hovhannisian was elected primate and served until 1928.
Bishop Khoren was given the title of Archbishop in December 1920, and designated chairman of the Supreme Ecclesiastical Council of Holy Etchmiadzin and locum tenens of the Catholicosate of All Armenians. He challenged the group called “Brotherhood of the Free Church,” which under the pretext of church reformation served as a tool of the Soviet Armenian regime.
After the death of Kevork V in 1930, Archbishop Muradbekian administered the Armenian Church for two years. The National Ecclesiastical Assembly elected him Catholicos of All Armenians on November 12, 1932.
Catholicos Khoren I struggled valiantly to reopen the churches closed by the government, to stop the destruction of churches and their use for non-religious purposes, and to prevent the persecution of Armenian clergymen by the Soviet authorities.
He also dealt with various issues regarding the statutes and the organization of the Church, as well as its rites. He worked to ensure a closer relationship between the hierarchical sees of the Armenian Church. He also organized the commemoration of the 1500th anniversary of the translation of the Bible (1935).

For one reason or another, the decisions were never put into practice. Archbishop Kevork Chorekjian, one of the few surviving high-ranking ecclesiastics, was named locum tenens. In 1941 he arranged for the remains of the unfortunate Catholicos to be buried near the main door of the Monastery of Saint Gayane. Fifty-five years later, in 1996, when the Soviet regime no longer existed and Armenia was an independent country, by order of the newly elected Catholicos of All Armenians, Karekin I, the remains of Khoren I were reinterred in the courtyard of the Cathedral of Holy Etchmiadzin.