For years the town was the leading edge of the American frontier, the jumping-off point for pioneers, visionaries and even a few scoundrels and fugitives. As the largest city in western North Carolina in the 18th and early 19th centuries, Salisbury was the major center of trade and politics. The coming of the railroad in 1859 further boosted the town's economy and stimulated industry.

Salisbury was twice occupied by enemy troops; in 1781 during the Revolutionary War by British General Cornwallis, and again in 1865 at the end of the Civil War by Union General Stoneman.