Because Wheeling was loyal to the Union during the Civil War, the first convention of delegates from the counties of northwestern Virginia met in Wheeling, May 13, 1861, which inaugurated the movement that resulted in the admission of West Virginia into the Union in 1863.

Wheeling was the capital of West Virginia from 1863 to 1870, when it was moved to Charleston. In 1875 the seat of government was again moved to Wheeling, and it remained there until 1885, when it was again changed to Charleston.

Wheeling's success as a industrial and manufacturing center was largely due to the abundance of cheap fuel in the area combined with the availability of water and railroad transportation systems needed to ship finished goods to market.

By the mid-1870's, Wheeling had a population of over 30,000 and several manufacturers producing cigars, malt liquors, glass, and various manufactured forms of iron. Six iron and nail factories located in Wheeling employed 2295 workers, producing 17,359 kegs of nails per week or about 902,200 per annum, with a market value of about $4,000,000 annually. Rolling mills for the manufacture of railroad bar, rod, hammer iron, sheet iron, bridge iron, and bolts were located in the town, as were two spike mills producing 50,000-60,000 kegs per annually. Wheeling's foundaries and machine shops employed 475 workers, while 60 persons were employed in extensive machine shops of the Baltimore & Ohio Railroad. Six large glass works employed 869 workers (including some women), and the amount of their products exceeded $600,000 per annum.

During the same era, two breweries were in operation, producing beer and ale, as was a distillery that produced 150 gallons of whiskey per day. Additional industries located in the town included two oil refineries, six tanneries, carriage and wagon factories, cigar and tobacco factories, a woolen mill, merchant flouring, sawing planing mills and sash factories, marble works, a calico printing establishment, drug laboratories, furniture, copperware, and harness and trunk factories. In addition, first class steamboats were built and completely finished in Wheeling shops.

Street cars were introduced in Wheeling in 1866, and by 1880 connected the extremities of the city and furnished a means of communications with all the towns lying within a radius of five miles from the city's center.

The Bloch Brothers Tobacco Company, of Wheeling, WV, originated outdoor advertising in 1890, when they began painting Mail Pouch Tobacco signs on bridges and barns across the nation.

Wheelings mainstreet in 1906

By the mid-1920's there were over over 200 industrial concerns in the city, employing over 9000 workers. The first radio station in West Virginia, WWVA, went on the air in Wheeling, WV in 1926. During the same era, a street-railway system and interurban lines linked Wheeling with its neighboring cities, with additional lines crossing the Ohio River serving cities in Ohio and Pennsylvania.