The college was established on November 30, 1850 by an act of the Mississippi state legislature and was named the Yalobusha Female Institute.

[2] Yalobusha was intended by Mississippi legislators to become the preeminent women's institution in the South and to draw students from throughout the region.

[3] Enrollment began in 1851, with 77 students of various Christian denominations attending Yalobusha from September through the end of June 1852.

[7][10] Under Holcombe's leadership, the Emma Mercer Institute emphasized "sound learning, without pretense and show" and "discipline and order, enforced by firmess, and courtesy.

[18] In 1936, financial troubles led the church to close the school and transfer its assets to Millsaps College.