In 1924, citizens in Cape Girardeau, Missouri formed a committee to build a non-denominational, non-profit community hospital in the city.

[2] In 1926, a group of 20 businessmen and physicians signed individual promissory notes to purchase a 52.5-acre (21.2 ha) tract of land for $8,250 from Emil Thilenius and Mrs. Anna Keller.

After the purchase, the two story farmhouse that stood on the current site of the hospital was moved down the hill to serve as the nursing quarters.

After the purchase of the farm, the committee sectioned off some of the land into lots for a new subdivision called Sunset Terrace.

The money from sale of the lots was applied to the unpaid balance of land and the rest was placed in a fund to be used for the hospital.

The name for Cape Girardeau's new hospital was chosen on the recommendation of the Southeast Missouri Medical Association.

This prediction by the Medical Association proved to be correct as 75% of the patients admitted during the first year of the hospital came from outside of the city of Cape Girardeau.

The Association realized that more money would have to be raised to provide a firm financial foundation for the hospital.

[2] Thieresia M. Norberg was hired as the hospital's first administrator a few months before the dedication with the salary of $50 per week plus "maintenance".

The first patient, Guy Lowes from Cape Girardeau County, was admitted to the hospital on January 9, 1928 for a tonsillectomy.

The infant girl weighed only 3 pounds, 9 ounces and was also the first occupant of the hospital's prized incubator.

Another new wing, part of a four-stage, five-year development program, was dedicated in 1973 to the west of the original hospital structure.

Dr. McPherron had previously served as the team physician at Virginia Tech and also at Western Carolina University.

In August 2019, SoutheastHealth and Southeast Missouri State University (SEMO) announced a new affiliation agreement whereby Southeast Health Orthopedics and Sports Medicine would be named the team physicians for all of the NCAA Division 1 athletics programs at SEMO as well as provide care for the students at the Holland College of Arts and Media for all of the performing arts students in the dance, theater, and music programs.