Greenwood Cemetery, on the National Road (U.S. 40) in Wheeling was incorporated in March 1866. Among the incorporators were Wheeling's Civil War mayor Andrew J. Sweeney, state founder Archibald W. Campbell, Dr. Eugene A. Hildreth, W. M. List, C. H. Berry, and other prominent citizens. The first interment was on July 22, 1866, for Caroline Morgan. Several bodies had been removed to Greenwood Cemetery prior to Morgan's burial.

James Gilchrist, a civil engineer, laid out the cemetery. Adorning the grounds with shrubbery, flowers, and trees, and enclosing the area with picket fences, he produced a park-like cemetery of the sort that became popular in the mid-19th century. Two cottages were built for the groundskeepers at the main entrance. Lots were sold, and Greenwood Cemetery went into business as a for-profit corporation. In 1919, Greenwood Cemetery became a nonprofit corporation and still maintains that status.

Greenwood Cemetery's grounds have been expanded from its original 37.5 acres and now include about 100 acres. The most recent addition to the cemetery is the 1983 Greenwood Chapel which was added to a 1909 receiving vault and is used for services during inclement weather. During the past century, numerous bodies have been re-interred at Greenwood when other cemeteries were taken by highways and other projects. More than 37,000 people are now buried in Greenwood Cemetery. Much of the story of Wheeling and the surrounding area can be gleaned from the gravestones.

The prominent citizens resting in Greenwood Cemetery include Campbell and Sweeney, as well as Mary Lovely Chapline Zane (1787-1858); the banker and cigarmaker Augustus Pollack (1830-1906); brewer Henry Schmulbach (1844-1915); Amelia Hay McElheran Sprigg (1785-1872); Stimpson H. Woodward (1812-1881); Capt. Samuel Sprigg Shriver (1843-1881); Tryphena Hornbrook (1821-1892); Dr. John Frissell (1810-1893); and department store founder Jacob C. Thomas (1822-1898).