He previously served as locum tenens, between 1923 and 1932, in the latter years of and after the death of Catholicos Gevorg V, and bishop of Yerevan from 1910 to 1924.

Among his teachers were prominent Armenian intellectuals Stepan Malkhasyants, Perch Proshian, and Makar Yekmalyan.

In August 1905 he was appointed head of the Armenian Church in western Georgia (Gori, Imereti, Batumi) and Ardvin.

[6] He traveled to the United States in 1920 to help reorganize the Armenian Church life there and raise funds for the First Republic of Armenia.

[9] During his reign, he tried to establish peace and improve relations with the dioceses in the Armenian diaspora and raise funds for the restoration of Etchmiadzin Cathedral.

[10] The New York Times wrote that Khoren was "regarded by fellow-Armenians as an able leader who had successfully reconciled his spiritual duties with his civil responsibilities as a Soviet citizen.

[12] According to the Armenian Church and post-Soviet historiography, he was strangled to death by NKVD agents in his bedroom at the Old Pontifical Residence (Veharan) in Etchmiadzin.

[34] According to Vazgen I, Catholicos from 1955 to 1994, Khoren I was killed on the orders of Viktor Khvorоstian, the Interior Minister of Soviet Armenia, who himself was executed shortly thereafter.

[35] Khvorstian claimed in June 1938 that Khoren I had died of a heart attack because he foresaw the end of his life and the catholicosate of Etchmiadzin.

[36] Vazgen I also noted that Grigor Harutiunian, the First Secretary of the Communist Party of Armenia in 1937–1953, had told him that Lavrentiy Beria was ultimately responsible for Khoren I's murder.

[37] His body remained at the residence for two days until he was buried at the cemetery of the nearby Saint Gayane Church by several nuns of Etchmiadzin.

[32] On September 7, 1996, the remains of Khoren I were reburied by Catholicos Karekin I near the entrance of Etchmiadzin Cathedral, next to other Catholicoi of the Armenian Church.