Veniaminov began his career, from 1824 until 1839, as a parish priest, first in Irkutsk, the capital of Eastern Siberia, and then in Alaska, which was part of the Russian Empire until 1867. While in Alaska, Veniaminov learned the Aleut language, for which he invented an alphabet and charted a grammar. His book The Way to the Kingdom of Heaven, written in Aleut in 1841, gained wide appeal. After spending 10 years in the Aleutians, he moved on to Novo Arkhangelsk (now Sitka) on Baronov Island and, in 1836, began to baptize the Kolosh Indians.

In 1840, while Veniaminov was in St. Petersburg to recruit support for the Alaska Mission, his wife died; he subsequently entered the novitiate, took the name Innocent, and was ordained bishop of the new Diocese of Kamchatka, which extended from the Kamchatka Peninsula to the Alaska Peninsula, including the Kuril and the Aleutian islands and the region of Yakutsk. For 28 years he travelled this region, learning the local languages, converting the inhabitants to Orthodoxy, and ultimately establishing four separate dioceses. He was rewarded with election to the position of metropolitan of Moscow in 1868, and in this role he established the Orthodox Missionary Society, which continued his work of conversion until the Russian Revolution.