Presbyterian missions to the Dakota tribe began in 1835 under the American Board of Commissioners for Foreign Missions (ABCFM). New School Presbyterians and Congregationalists assisted with staffing and funding as the American Board worked with Dakota and other North American Indian tribes. The American Board gradually reduced its activities with American Indians during the period 1837-1869, transferring most of its work with the Dakota to the Presbyterian Board in 1870. The balance of the American Board's work among the Dakota was transferred to the American Missionary Association in 1883.

The first missionaries to the Dakota were the Reverend Dr. and Mrs. Thomas Williamson and the Reverend and Mrs. J. D. Stevens, who established stations at Lake Harriet and Lac qui Parle. The first Presbyterian church was established among the Dakotas at Lac qui Parle, Minnesota, in 1836. Work progressed slowly, but by 1850 there were three organized churches and thirty-one communicants.

Mission work continued concurrent with the growth of fully constitutional bodies among the Dakota. In 1844 the Presbytery of Dakota, which had its roots in missionary work, was organized. The New School Synod of Minnesota was formed in 1858, consisting of the presbyteries of Dakota, Minnesota, and Blue Earth. The Old School and New School synods merged into one at the time of the union of 1870. At this time the Presbytery of Dakota reported seven churches with 628 members. In 1885, John P. Williamson reported to the Home Board that the Indian Presbytery of Dakota had eleven churches and 700 members, and that nine out of twelve ministers were Native American. The Dakota Presbytery was reorganized in the 1880s as a Native American presbytery, independent of geographic boundaries.

In 1870-71 a portion of the Dakota Mission was transferred by the American Board to the Board of Foreign Missions (PCUSA). Within the first year, Thomas Williamson and his son John had opened two new churches, one at Flandreau and one at Greenwood. W. O. Rogers, a Dakota Indian, was pastor of the Greenwood church. The Flandreau congregation was made up of Santee tribe members who had moved from the Nebraska Territory. John Eastman, a native, was installed as pastor at Flandreau in 1877.

Miss Jennie B. Dickson and Miss Charlotte C. McCreight opened a school at Poplar Creek, Montana, in 1880, and in 1886 they moved on to Pine Ridge, South Dakota, to start another one. A further mission station opened at Wolf Point, Montana, in 1885. The Good Will Mission was established by Rev. Stephen R. Riggs in 1870 under the auspices of the Dry Wood church in South Dakota. The mission served as an industrial and training school for Sioux boys and girls.

Mission work with the Dakota was transferred from the Board of Foreign Missions to the Board of Home Missions in the 1880s, and in 1923 all mission work with Native Americans was transferred to the newly created Board of National Missions.