On [[December 30]], 1844, St. Innocent appointed him head of the new Kvikhpak Mission to bring the light of Christ to the people along the Yukon River. With two young Creole assistants, Innokentii Shayashnikov and Konstantin Lukin, and his nephew Vasili Netsvetov, Father Jacob established his headquarters in the Yup'ik Eskimo village of Ikogmiute. From there, now known as Russian Mission, he traveled to the settlements for hundreds of miles along the Yukon and Kuskokwim Rivers, visiting the inhabitants of settlements along the way. For the next twenty years he learned new languages, met new people and cultures, invented another alphabet, and built more churches and communities. At the invitation of the native leaders he traveled as far as the Innoko River baptizing hundreds from many, and often formerly hostile, tribes. He continued even as his health deteriorated.

During his last missionary travels in the Kuskokwim/Yukon delta region he is remembered for baptizing 1,320 people and for distinguishing himself as the evangelizer of the Yup'k Eskimo and Athabascan peoples.