Keyser was originally called Paddy Town after Patrick McCarty, son of one of the original settlers. With the coming of the Baltimore and Ohio Railroad in 1852, the destiny of the area changed from a quiet rural community to a thriving industrial center. The name was changed to New Creek Station and then to New Creek. In 1861 the Civil War came rumbling through the valley. Fort Fuller was built on the present site of Potomac State College, and Fort Piano entrenchments were established on New Creek Mountain. Because of the importance of the railroad, the town changed hands 14 times.
When West Virginia became a state in 1863, there was some contention between Piedmont and New Creek over the location of the county seat. As an inducement to have the county seat located in New Creek, the Davis brothers donated land for the courthouse in 1867.
In 1874, the town was incorporated as Keyser after William Keyser, vice president of the Baltimore and Ohio Railroad.