In 1900, Patrick J. Donahue, West Virginia's Roman Catholic bishop, founded St. Joseph's Hospital. It was originally located in the old Visitation Convent at Avery and Fifth streets in Parkersburg. The convent was renovated, and the hospital opened with 21 beds. Four Sisters of Saint Joseph of Wheeling and two assistant nurses were invited to Parkersburg to run the new hospital. Sister Immaculate Feeney was the first administrator; she had served at Wheeling Hospital during the Civil War. The hospital's nursing school opened in 1905 and operated until 1969. Many of the hospital's patients were charity cases.

The constant flow of patients necessitated the addition of a new wing in 1903, followed by a second wing in 1924. By 1929, St. Joseph's administrators decided to build a new hospital. A building committee of hospital doctors and prominent Parkersburg businessmen conducted a city-wide campaign to raise $300,000 for the new facility. The committee realized its goal within ten days, despite the recent stock market crash. The new hospital was built on the old McConahey estate at 19th Street and Murdoch Avenue, on an elevation overlooking the Ohio River. The new six-story brick structure was built for $600,000 in a colonial design with three acres of landscaped grounds. St. Joseph's bed capacity rose from 100 to 170. The C. Z. Ruth Memorial Annex was built in 1962 to accommodate major services including inpatient and outpatient facilities.

In the late 1960s, St. Joseph's administrators developed a long-range plan for expanded hospital facilities. In 1977, the completion of a $20 million construction and remodeling program increased the number of hospital beds to 216, along with additional clinics and expanded hospital services. In 1996, the Sisters of Saint Joseph entered into a joint venture with Columbia HCA, and by 2001 their governance role in the hospital ended. The hospital was acquired by the Signature Hospital Corporation of Houston, Texas, in April 2007. In 2011, St. Joseph’s joined the West Virginia United Health System, along with another Parkersburg hospital, Camden-Clark Memorial Hospital, and became the St. Joseph's Campus of the Camden Clark Medical Center. The St. Joseph’s Campus closed permanently in 2014. The Camden Clark Medical Center is now part of WVU Medicine.

In 2021, six buildings of the former hospital were dedicated as St. Joseph’s Landing, an 850,000 square-foot business campus in Parkersburg.