St. Mary's Hospital, now St. Mary's Medical Center, in Huntington, was opened November 6, 1924, by eight Pallottine Missionary Sisters. The founding sisters had left their home in Bremerhaven, Germany, and barely missed sailing on the doomed Titanic, coming eventually to New York state where they learned English from the Sisters of St. Francis. They came to West Virginia in August of 1912 to open Holy Family School in Richwood and then opened Sacred Heart Hospital in 1913. The next step was to open St. Joseph's Hospital in Buckhannon in 1921, and then the sisters came to Huntington to open St. Mary's, a 35-bed nonprofit facility.

The School of Nursing on the hospital grounds was added in 1929, and today the 393-bed hospital is the third-largest in the state. It is the largest private employer in Cabell County and is recognized as a regional leader in comprehensive cardiac care, with more than 550 open-heart surgeries annually. Its most recent addition is a $17 million, 75,000-square foot outpatient center which opened July 28, 1997. The hospital opened its new radiation oncology center in 1999.

On November 4, 1997, St. Mary's announced it would join an alliance with Cabell Huntington Hospital and Pleasant Valley Hospital in Point Pleasant to reduce operating costs and protect against the possibility of a buyout by a national hospital chain. The new group, Genesis Affiliated Health Services, Inc. was given $1.25 million by each of the three hospitals to cover start-up costs and administrative expenses. Dissatisfaction with the arrangement arose, and Genesis was dissolved in 2002.

In August 2014 the Pallottine Missionary Sisters announced they were dropping their 90-year sponsorship of St. Mary’s. In November St. Mary’s Medical Center agreed to merge with Cabell Huntington. The merger was opposed first by the Federal Trade Commission and, later by state businesses. In January 2018, all parties reached a compromise approving the merger. In March, the Vatican approved the transfer of sponsorship. St. Mary’s retains its name and Catholic affiliation. The two hospitals will be unified under a new, single healthcare system while keeping their individual identities.