Saint Francis Hospital in Charleston was founded in 1913 by Patrick J. Donahue, West Virginia's Roman Catholic bishop. The Laidley estate at 333 Laidley Street was purchased and renovations to create a hospital were overseen by Father Lewis Centner, pastor of Sacred Heart Church in Charleston. A group of Franciscan Sisters arrived from Williamsville, New York, on December 13, 1913, to manage the hospital, which opened January 15, 1914. Saint Francis has remained at its original location throughout its history.

Within two years of the opening of Saint Francis Hospital, it became necessary to construct a new facility to meet the growing demand. The new hospital opened January 24, 1917, with 71 beds, operating rooms, x-ray machines, laboratories, a chapel, and a chaplain's apartment. Saint Francis Nursing School opened in January 1915 and graduated its first class in January 1917; the nursing school closed in 1961.

In 1921, the Franciscan Sisters were recalled to New York, and the Sisters of Saint Joseph of Wheeling took over the hospital. In 1924, money from the John B. Crowley estate paid for a new addition. New nursing school facilities were built in 1939 and were designed to be converted into hospital space if necessary. By 1950, Saint Francis had 130 beds. A 1971 extended care facility increased the bed capacity to 187; this was quickly converted to an acute care facility which called attention to the drastic demand for more beds.

In 1975, the board of directors developed plans for a long-range construction project to meet the rapid changes of modern medicine and provide more space for patients. The plans called for the construction of a new patient tower, parking garage, medical office building, renovation of the 1971 building, removal of the 1917 brick hospital, and establishment of a garden entrance. Additional hospital services and clinics were added, and by 1990 Saint Francis Hospital had been transformed to the modern medical complex familiar to Charlestonians today. In 1995, the Sisters of Saint Joseph of Wheeling sold Saint Francis Hospital to Columbia HCA. In 2005, Saint Francis was bought by LifePoint Hospitals of Tennessee.

In 2007, it was purchased by Thomas Memorial Hospital and became part of a new organization, Thomas Health System. In 2022, the boards of directors of Thomas Health, Thomas Memorial, and Saint Francis voted to become affiliates of WVU Medicine, which opened Saint Francis as "the state's first full-service and comprehensive orthopedic hospital" in October 2024.