Monroe County encompasses 473.5 square miles of the southeastern portion of West Virginia, the Virginia border being its eastern and southern boundary. The New River separates Monroe County from Mercer County. The western end of Monroe County became part of Summers County in 1871. Greenbrier County is to the north. The Great Eastern Divide runs through Monroe County, separating the watersheds of the Atlantic and the Gulf of Mexico.

Monroe was segmented from Greenbrier County against the objections of the mother county. Nevertheless, the Virginia General Assembly passed the bill to establish the new county on January 15, 1799. It was named for James Monroe, the newly inaugurated governor of Virginia and later president of the United States. In the future, 15 counties across the nation shared the name Monroe, but this was the first one and the only one that James Monroe himself signed into being.

The selection of a county seat was a problem. There were no towns, but James Alexander's farm along the heavily traveled north-south Indian trading path was well placed for one. Alexander entered into a bond to convey one acre for a courthouse and an adjacent ten acres for a town. Despite objections that the site was not centrally located, a courthouse and a jail were constructed, and the town of Union came into existence. The name, which became an ironic one when Monroe County preferred the Confederacy in the Civil War, is said to have been chosen because it was the point of union or mustering place for the militia.

The presence of small mounds scattered about the southern end of the county suggests Monroe County's prehistory. It is generally accepted that this area was a hunting ground for various Indian tribes at the time of the arrival of the first European-American settlers. These first Europeans were Scotch-Irish and Germans from the Shenandoah Valley. Many had received land grants for service during the French and Indian War. Others had been enticed by the efforts of various land-holding companies.

The new county prospered with the young nation. Waterpower meant mills, and there was no shortage of waterpower in Monroe County. At one time Second Creek had a mill for each of its 18 miles. Indian, Laurel, Turkey, Rich, and Wolf creeks also contributed their power. Gristmills, sawmills, and woolen mills thrived. The limestone country produced fine spring water, abundant grass for grazing, and sweet soil for growing crops. Within the caves beneath the land was saltpeter (potassium nitrate) for the manufacture of gunpowder, a very early industry that supplied powder for the Revolutionary War and later the Confederate Army.

During the Civil War, Monroe County favored the South. Ninety-five percent of men eligible for military service were in one of the 12 locally formed units that served the Confederate States. As a result of its Southern allegiance Monroe County was occupied by Union forces for three years after the war.

The early settlers established Presbyterian, Baptist, and Methodist churches. Rehoboth Church (1784) still stands as the oldest church building west of the Alleghenies. Education came with the first settlers, and a schoolmaster was among the victims of the 1755 massacre at Baughman's Fort on the Greenbrier River. The Literary Fund established by the Virginia Assembly in 1809 was the beginning of public education. The Union Academy, established in 1820 to teach a classical education, existed until 1861. Attempts to revive the school after the Civil War were unsuccessful.

Spas and resorts developed around Monroe's mineral springs, most notably Sweet Springs, Salt Sulphur Springs, and Red Sulphur Springs. They catered to a clientele from the eastern and southern states. While each of the resorts advertised its water for specific ailments, many of the visitors sought to escape the malaria and yellow fever that plagued the coastal cities or simply the heat and humidity of the lower country. After the Civil War the springs never regained their antebellum grandeur. The elegant Jeffersonian architecture of the Old Sweet Springs and the formidable stone buildings of Salt Sulphur Springs remain as monuments to past glory. In the late 20th century, spring water regained a place in the economy of Monroe County through the bottled water industry, drawn mostly from the seemingly limitless aquifer beneath Peters Mountain. The Sweet Springs Water Company has won the gold medal several times at the international water tasting festival held annually at Berkeley Springs.

Two U.S. senators were among notable Monroe Countians. Allen Taylor Caperton first served as a senator to the Confederate States from 1861 to 1865. After amnesty was granted he was elected to the U.S. Senate, where he died in office in 1876. Frank Hereford of Union succeeded him. Anne Royall, one of the first female journalists in America, lived much of her early life at Sweet Springs. Col. Andrew Summers Rowan, famous for carrying the "Message to Garcia" in the Spanish-American War, was from Monroe.

Modern Monroe is a farming county. Monroe Countians formed the first Corn Club in West Virginia in 1907, the beginning of the 4-H clubs in the state. Livestock farming—namely cattle, dairy, and sheep farming—keep pace with the crop farming of hay, corn, oats, wheat, and tobacco. Timber is also a major contributor to the economy. In recent years large natural gas deposits have been found.

Monroe County’s population has remained relatively steady since the late 1800s. Its 2020 population was 12,376.

In 2023, Monroe County's largest employers were the county school system, the Goodrich Corporation rubber fabrication plant in Union, Monroe County Health Center, Twenty/20 Management, and WVNH Emp (Worthington Health Care Center). In addition, many Monroe Countians work at The Greenbrier resort at White Sulphur Springs, the Celenese plant at Narrows, Virginia, and the WestRock (formerly MeadWestvaco) paper mill at Covington, Virginia. Creekside Resort on Indian Creek, High Meadow Lodge at Wolf Creek, and the cottages at Salt Sulphur attract visitors to the county. An 18-hole golf course has been developed at Lindside, south of Union.

Tranquility has always been the password to Monroe County. For one recent period the county had the lowest crime rate in the state, and the second-lowest crime rate of any county in the United States.