De Paul Hospital, which was formerly located at 2415 North Kingshighway, is the oldest existing Catholic hospital in the country, as well as being the first institution of its kind west of the Mississippi. It was founded in November 1828, by the Sisters of Charity of St. Vincent de Paul on a site donated by John Mullanphy, on Spruce Street between Third and Fourth. Originally occupying small buildings on the lot, in 1832 a large three story building at the same location was completed. For many years it was known as the Sisters' Hospital and was operated on a semi-charitable basis.

Business encroachments made the old site ill-adapted for hospital use, so that in 1874 a larger building was completed for the hospital at Montgomery and Coleman Streets. While at that location it was known as the St. Louis Mullanphy Hospital, and its School of Nursing was founded there in 1894. This building was severely damaged by the tornado of September 29, 1927, necessitating another move. The building on North Kingshighway was occupied in 1929 and has been considerably expanded since, notably by a new nursing school building at 5050 Highland Avenue in 1951. In 1977 De Paul Hospital relocated in a new complex at 12303 De Paul Drive in St. Louis County. Later, an unsuccessful attempt was made to open another hospital in the building on Kingshighway, which is being transformed into a Senior Citizens Center.