St. James Parish, completed by 1823, was the first church built in the Diocese. Initial members of the parish were primarily Irish and German immigrants. A second church was built in 1849. When the Diocese of Wheeling was created in 1850, St. James became the cathedral parish. The name of the parish was officially changed to St. Joseph in 1872.

Grade schools were open for both the boys and girls of the parish by 1848 and high schools by 1865. Central Catholic High School was established in 1898. The Cathedral Parish School became Wheeling Catholic Elementary School in 1988 and closed in 2011. Over the years the schools were staffed by the Sisters of St. Joseph, Xaverian Brothers, Marist Brothers, and lay teachers.

St. Joseph Cathedral has been a center of Catholic life and Wheeling in the diocese from the time it's humble wood frame (1823) to the majesty of its Romanesque carved stone (1926). All city parishes and many of the Northern Panhandle were formed from the cathedral. In the 1920s alone four congregations sprung from the Cathedral to serve the influx of immigrants into the city: Saint Anthony Parish (East Wheeling) was closed in 1968; Sacred Heart (North Wheeling), St. Joan of Arc (Fulton) and Blessed Trinity (Island) were closed in 1995.