Around the 1920s, the need for a new and larger hospital in Knoxville encouraged the community to come together in support of constructing the new and modern St Mary’s Hospital in North Knoxville. Daniel Dewine donated seven acres of property in 1926. The Sisters of Mercy of the Cincinnati Province, in conjunction with the Catholic Diocese of Nashville, began raising funds to build a hospital on this property at the end of 1927.

Right as construction began, the Great Depression hit and half of the money pledged could not be collected, forcing the hospital’s original design to be downgraded. On the day of its dedication, April 22, 1930, St. Mary’s Hospital saw a crowd of 40,000 Knoxvillians to celebrate its opening. By the end of the year, the hospital had admitted 1,484 patients. In the following decade, St. Mary’s Hospital saw much success and opened a School of Nursing on its campus. The first class, amounting to twelve students, graduated in 1933. The hospital experienced numerous changes to its campus and administration throughout the years. Many new buildings and additions were constructed in response to community needs and developments in the medical field. As the hospital grew and expanded, the Sisters of Mercy organized their health ministry into Mercy Health Care System, later renamed to Catholic Health Partners in 1997.

In 2011 St. Mary’s Hospital was sold to a for-profit hospital organization, Health Management Associates Inc., and the name was changed to Physicians Regional Medical Center. The Sisters of Mercy remained on campus and continued to serve the hospital. The money from this sale established St. Mary’s Legacy Foundation which later purchased St. Mary’s legacy mobile clinic.