Lewis County, located in north-central West Virginia at the crossroads of Interstate 79 and U.S. 33, was created from part of Harrison County on December 18, 1816. Named for Col. Charles Lewis, killed in the Battle of Point Pleasant, it was a huge territory from which were later formed all or parts of six other counties. Modern Lewis County has an area of 389.5 square miles. The population in 2020 was 17,033, its highest total since 1990.

People of European descent first settled in present Lewis County in 1769. Mostly of Scotch-Irish, German, and English lineage, they included John Hacker and Indian fighter Jesse Hughes. The first courts were conducted in 1816 in the hamlet of Westfield on the new county's northern edge. To establish a more central seat of government, one year later the county purchased the farm of pioneer settler Henry Flesher, at the confluence of the West Fork River and Stonecoal Creek. The new county seat was initially called Preston, then briefly renamed Fleshersville, and finally, in 1819, Weston.

In its first 30 years, Lewis County's economy was based largely on a self-sustaining agriculture. The primitive roads limited trade with distant points. The building of turnpikes through the county in the mid-1840s improved business and made Lewis County an important commercial and political center. The town of Jane Lew was established. Weston's first church building was erected in 1844; the first newspaper began publishing in 1846; the first bank opened its doors in 1852; and the first school was built in 1855.

The county's representatives in the Virginia legislature were able to secure the state's first major investment of money west of the mountains, with the locating at Weston of Virginia's third asylum for people with mental illnesses. Construction of Weston Hospital began in 1859 but was halted by the outbreak of the Civil War. In June 1861, federal troops seized the gold deposited by Virginia in a Weston bank for the construction project. The gold was taken to Wheeling for the use of the loyalist Reorganized Government of Virginia.

Lewis Countians were divided in their loyalties during the Civil War. Thomas J. "Stonewall" Jackson had grown up at Jackson's Mill. His service to the South gave heart to the small local elite, the doctors, lawyers, and a good number of the merchants, many of whom had roots in Tidewater Virginia. The greater number of people, the less affluent, were loyal to the Union. They had as their hero U.S. Gen. J.A.J. Lightburn, who had grown up near Weston. The war years passed in alternate occupations by loyal and rebel forces; arguments and violent clashes between neighbors and within families; arrests and internments; and a few bushwhackings.

After West Virginia's creation in 1863, the new state government resumed the asylum project and completed it in 1880. For 50 years, until the beginning of World War I, Weston Hospital was the largest single item in the state budget. It made Lewis one of West Virginia's most prosperous counties.

Commerce generated by the hospital made feasible the building of a branch railroad, a narrow-gauge connecting Weston with the Baltimore & Ohio at Clarksburg, in 1879. Farmers could then ship their produce to the most distant markets at reasonable costs. Local livestock found a market as far away as Europe. One of the state's earliest telephone systems was installed in 1885. By 1890, municipal water and sewer systems were under construction; electric lights and paved streets followed. At the same time, the branch railroad, now called the West Virginia & Pittsburgh, was being converted to standard gauge and extended south to Sutton and Richwood. Weston was its headquarters and also headquarters for several companies engaged in central West Virginia's timber industry. Lewis County is heavily forested with valuable hardwoods.

Weston's first public school building was erected in 1872. Ten years later, a smaller structure was built for African-American children. Lewis County's first high school was established in 1895 at Weston. Other high schools were built, in 1912 at Jane Lew and at Walkersville in 1920. In 1914, the county's Catholic population built a school in Weston. Most recently a new middle high school was erected in Weston, a new county high school at Bendale, and a new elementary school at McGuire Park.

About 1900, oil and natural gas in fabulous quantities were found deep under Lewis County, creating an overnight boom. Cheap gas attracted several glass manufacturers to the county, the earliest ones making window glass, the later ones beverage glassware. Weston and Jane Lew continue to be centers of natural gas production, storage, and transportation, and glass manufacturing.

Lewis County lies between the major northern and southern coalfields of West Virginia. However, some coal of lesser quality began to be mined near Walkersville as early as 1907, and strip mining of coal occurred in all parts of the county following World War II and continued for 30 years.

In 1913, Weston became the southern terminus of regional electric trolley car service, connecting it and Jane Lew on an hourly schedule with Clarksburg and Fairmont. The first paved roads were built in the mid-1920s. Weston's Main Avenue remained a thriving commercial center until the development of malls and superstores in other counties, and more recently in the county but outside the city. The development of modern highways made the railroad less important, and the rails linking Weston with Clarksburg and Buckhannon were taken up. A branch line continues to operate across the southern part of the county, hauling coal from Braxton, Webster, and Nicholas counties to the CSX main line at Grafton.

Weston State Hospital closed in 1994. Lewis County remains a center for medical care, with the completion in 1972 of the Stonewall Jackson Memorial Hospital and the opening in 1994 of the William R. Sharpe Jr. Hospital for individuals “committed . . . through civil commitment or, in the case of forensic patients, ordered through the judicial system.” Medical care for central West Virginians is today one of the county's chief sources of employment and income.

The county's potential for tourism is only beginning to be realized, with 1-79 and Corridor H (U.S. 33 east) placing it within a day's drive of half of America's population. New motels and restaurants now operate on those highways. The development of Stonewall Jackson Lake and Dam brought major change to southeastern Lewis County in the late 20th century. The dam, originally opposed by local residents facing displacement, was completed in 1988. Stonewall Jackson Lake State Park, one of West Virginia's premier resort parks, opened in 2002.

In 2023, Lewis County's largest employers were the county school system, the William R. Sharpe Jr. Hospital, Vandalia Health (CAMC), Walmart, and Benchmark Conference Centers.