St. Marys is a Yup'ik Eskimo community on the north bank of the Andreafsky River, 5 miles from its confluence with the Yukon River. The history of the village and the Roman Catholic Church there are inextricably linked.

In 1893, missionary priests from the Society of Jesus set up a mission school at Akulurak, 90 miles downriver from Andreafsky. Akulurak means "in between place," aptly describing the village, which was on an island in a slough connecting two arms of the Yukon River. Sisters of St. Ann staffed the school, but they left in 1898 and the school closed. It reopened in 1905, this time with Ursuline Sisters. The school flourished, partly because diphtheria and influenza epidemics racked the region and left many orphans at the boarding school.

Over the years, the slough surrounding Akulurak silted in severely. In 1948, the missionaries decided to move to higher ground, this time near Andreafsky. Materials from an abandoned hotel built during the gold rush were used to construct the new mission. In 1949, an unused 15' by 30' building and other materials from Galena Air Force Station were barged to Saint Marys. These materials were used to construct a school. The parents of Saint Marys'students, who lived in Akulurak, wanted to be nearer to their children so most of the Akulurak villagers also relocated to the newly founded Saint Marys village. The Jesuit priests and Ursuline Sisters subsequently operated Saint Marys Boarding School until it was closed in 1987. The school was renowned for its excellence as a college prep school for the Alaska Native high school students of the lower Yukon region. It was sold in 2003 to Ciunerkiurvik Corporation.

Meantime, St. Mary's school chapel served two separate worshipping communities for two decades, the students of the school, and the residents of the village. The parishioners of Saint Marys felt the need to establish a separate identity as a parish. In 1970, a parish council was established, and plans for the new church began. The new parish, Church of the Nativity, was completed in 1973.

The Church of the Nativity has been served by Jesuits priests since it was first established.

The region remains a hub of missionary activity. From St. Marys, a Jesuit priest and two Franciscan Sisters, along with a small support staff, oversee three vital Diocesan ministry programs that are headquartered there: the Native Ministry Training Program; the Rural Deacon Program; and the Coordination of Rural Ministry for all four Subregions of the Yukon-Kuskokwim Delta.