Keyser, the county seat of Mineral County, is located on the North Branch of the Potomac River in the Eastern Panhandle of West Virginia. The place was first called Paddy Town, supposedly for Patrick McCarty, an early landowner who operated a nearby iron furnace. Later the community was called New Creek, for the creek that joins the North Branch at this location.

The first people of European descent to pass through present Keyser are believed to have been William Mayo and George Savage, sent by Lord Fairfax in 1736 to seek out the source of the Potomac River. The first local land grant was issued by Fairfax to Christopher Beelor on March 20, 1752. Early industry included an iron furnace and foundry, a salt well, and a salt-making plant. The town received an economic boost with the arrival of the Baltimore & Ohio (B&O) Railroad in 1852, and was renamed for B&O official William Keyser. Mineral County was created in 1866, with Keyser as its county seat.

The Civil War came to Keyser in 1861. Fort Fuller was built on the present site of Potomac State College of West Virginia University. Keyser changed hands 14 times during the war due to the importance of the railroad.

Keyser, elevation 809 feet, was incorporated in 1913. In 2020, its population was 4,853, a 10.8 percent decline from 2010. State Route 46 intersects with U.S. 220 at Keyser, with the latter road then crossing the Potomac into Maryland.