Tyler County lies on the Ohio River between Wetzel and Pleasants counties. It was formed from Ohio County on December 6, 1814, originally encompassing all of what is now Wetzel County and parts of present Doddridge and Pleasants. Tyler County was named for John Tyler, governor of Virginia (1808-11) and father of President John Tyler.

Bordered to the west by the Ohio River's Long Reach—a straight stretch in the river from Paden City to Raven Rock—Tyler County is drained largely by Middle Island Creek and its tributaries. Although there are elevations approaching 1,500 feet along Tyler's borders with Wetzel and Doddridge counties, the highest point within Tyler County is the knob known as the Owlshead at 1,444 feet above sea level. The elevation at Bens Run, on the Ohio River in the southwest corner of Tyler County, is 620 feet. Tyler County is hilly, its terrain sculpted by valleys and hollows. There are several large Ohio River islands in the county, including Williamson Island south of Paden City.

At 260.7 square miles, Tyler County historically had six magisterial districts: Lincoln, Union, Ellsworth, McElroy, Centerville, and Meade. Today, it has four: North, South, West, and Central. In addition to Sistersville and Middlebourne, the county's communities include Friendly, Bens Run, Alma, Shirley, Josephs Mills, and Wick. In 1937, the women of Friendly were successful in their campaign to seat an all-female municipal government. The Tyler-Wetzel county line divides Paden City, which otherwise would be the largest town in the county.

European-American hunters settled in what became Tyler County in 1792 near the present town of Friendly. Mainly of Scotch-Irish, English, and German descent, other settlers from the East soon flowed into the former Indian hunting grounds. By 1800 Henry Jolley had established a ferry across the Ohio River at Sistersville. The Bens Run earthworks, an archeological site, is evidence of rich prehistoric activity.

Charles Wells founded the oldest of Tyler County's communities in 1802. Wells Landing was later named Sistersville, after Wells's daughters, Sarah and Deliah. It was the first county seat and remains the largest town in Tyler County. In 1895, Charles Wells's grandson, Ephraim Wells, opened the Wells Inn in downtown Sistersville. Still a local landmark, the red-brick hotel was added to the National Register of Historic Places in 1972.

In 1815, centrally located Middlebourne became the county seat of Tyler County. Robert Gorrell had founded Middlebourne in 1798.

The oil and gas industry transformed the region in the late 19th and early 20th centuries. In 1892, the Polecat well was drilled into one of the richest oil pools in West Virginia. In 1894, the Big Moses gas well was drilled and became one of the largest ever found. What followed was an oil and gas rush that increased the population of Sistersville from 1,000 to 7,000 by the end of the decade, while the population of the county grew from 11,962 to 18,252. By 1910, the oil and gas boom was declining, and the effect was felt throughout the county.

Other small industries, such as gristmills and sawmills, chemicals, glass, and pottery, dotted the county during the 1900s. Many residents still worked family farms or in the downsized petroleum industry. Currently, many of Tyler County's residents work in manufacturing, often commuting across the Ohio River to plants on the Ohio side. In 2023, Tyler County's largest employers were Momentive Performance Materials, the county school system, Quality Carriers, the county commission, and Real Alloy Recycling.

Today, the county is a quiet, largely rural society. Tyler Countians have a home ownership rate of 84 percent, higher than the state and much higher than the nation as a whole. Household income is about the same as for the state, and the county's poverty rate is lower then the state's. Tyler County’s population was 8,313 in 2020.

Tyler Countians have made their mark in the larger world. Though not born there, West Virginia's first governor, Arthur I. Boreman, received his early education in Middlebourne. Pitcher Wilbur "Lefty" Cooper, who spent 12 years with the Pittsburgh Pirates, was born on Davis Run in 1892. Gov. Cecil H. Underwood was born in 1922 near Josephs Mills. Underwood, a Republican, was both the oldest and youngest governor West Virginia has had.

Today, students from all over the county attend Tyler County Consolidated Middle and High schools. Sistersville General Hospital, founded in 1908, continues to provide care for the entire county. Tyler County Speedway, at the Tyler County Fairgrounds, is one of the few dirt tracks for auto racing in the tri-state area. History buffs from across the country travel each year to Sistersville's Oil and Gas Festival, which celebrates the area's industrial heritage.