Orthodox Christianity includes independent, national apostolic churches that exist in communion with each other but not with the Roman Catholic Church. Although practices vary, Orthodox Christians have much in common with Roman Catholics, with the important difference that they do not accept the supremacy of the Pope. Orthodox churches with a formal presence in West Virginia are the Antiochian, the Carpatho-Russian, the Greek, and the Serbian, each with its distinct hierarchy in North America.

In 1768, Orthodox Christians first colonized what is now the United States with a church in Florida. As early as 1880, Orthodox Christians from Russia, Greece, and the Ottoman Empire began to settle in the coalfields of southern West Virginia. Later, they came to work in the mines and steel mills in the northern part of the state.

West Virginia's first Orthodox Christians held prayer services in private homes. Soon, they built churches and imported priests to conduct liturgies in their native languages and to serve their spiritual needs. St. Mary Carpatho-Russian Orthodox Church, first in Elkhorn, McDowell County, and now located in Bluefield, was founded in 1880 and developed into a formal community by 1895. In 1892, Syrian and Lebanese immigrants founded St. George Orthodox Church in Charleston, the oldest and largest Antiochian presence in West Virginia. Greeks founded six congregations that continued to exist in 2003.

Small Orthodox parishes were founded in Logan and McDowell counties in the early 1900s and withered away. Only West Virginia's largest cities were able to retain Orthodox churches of the various jurisdictions. In 2004, West Virginia had established Orthodox communities in Beckley, Bluefield, Charleston, Clarksburg, Huntington, Morgantown, Weirton, and Wheeling. Eleven individual churches were listed in a 2000 church survey, with an estimated 4,310 adherents.

In the late 1990s, nearly a dozen monks of the Russian Orthodox Church Outside of Russia founded the Holy Cross Skete or hermitage in Wayne County. The Russian Orthodox Church Outside of Russia broke away from the Russian Orthodox Church during the Bolshevik revolution, but the two churches reconciled in 2007.