Named for James Wood, Virginia's governor from 1796 to 1800, Wood County was established by the Virginia General Assembly on December 21, 1798, a little over 13 years after the first permanent European-American settlement (Neal's Station) had been founded in the county. The county seat is Parkersburg.

Reduced in size between 1831 and 1863 by the creation of Jackson, Roane, Ritchie, Wirt, and Pleasants counties, Wood's remaining 377 square miles is divided almost equally into northern and southern sectors by the Little Kanawha River. The county was in 1863 the home of four of the founders of West Virginia: Arthur Ingraham Boreman (the state's first governor), William Erskine Stevenson (the first president of the state senate), Peter Godwin Van Winkle (one of the state's first two U.S. senators), and Jacob Beeson Blair (a member of the U.S. House of Representatives). It was also the home of the state's first federal judge, John Jay Jackson Jr.

Population increased steadily in the antebellum period, due to the completion of internal improvements and several important discoveries. Wood is located at the confluence of the Ohio and the Little Kanawha, and the introduction of the steamboat on the Ohio in 1811 increased trade through the county. The local economy was boosted by the completion of two turnpikes by 1847 and the Northwestern Virginia Railroad (later part of the Baltimore & Ohio Railroad) to Parkersburg a decade later. The discovery of petroleum in the area gave an additional spark to the economy. As a result of these developments, Wood County attracted a diverse population, including the largest Irish Catholic, German, Jewish, and Black settlements between Wheeling and Huntington.

Within two months of the outbreak of the Civil War in 1861, federal forces were stationed in the county to protect the railroad. Later, three hospitals were established. In 1863, Fort Boreman was constructed, an installation built on a hill overlooking the point where the Little Kanawha and the Ohio meet.

After the war's end in 1865, the number of Wood County's residents increased every decade until the 1980s when the population peaked at 93,648. Its population in 2020 was 84,296. Its growth in 1865-1900 was fueled by the large reserves of oil and natural gas in the Mid-Ohio Valley, the construction of refineries, the completion of the Ohio River Railroad in 1884, and the development of a vigorous timber processing industry. Growth has been sustained by economic diversification and education.

In 2023, Wood County's largest employers were WVU Medicine, the county school system, Walmart, Chemours (DuPont), and Linx Community Services

The county ranks near the top in the state in educational leadership. In Parkersburg the first free school south of the Mason-Dixon line was established in 1862 for African Americans, the first public high school diplomas issued in the state were awarded to Parkersburg High School graduates in 1874, and the first high school diplomas to be issued to African Americans were granted at Sumner School in 1887. Wood has four high schools: three public and one private. It has one baccalaureate degree-granting college: West Virginia University at Parkersburg, founded in 1961. Mountain State College, established in 1888, offers associate’s degrees for medical assistants and individuals who work with people with dependency disorders. Another degree-granting organization, the private Christian school Ohio Valley University, operated from 1958 until closing in 2022.

Most Wood Countians live to the west of Interstate 77, which divides the county from east to west, in Parkersburg, Vienna, Williamstown, and North Hills, the county's four incorporated communities. The county's Parks and Recreation Commission oversees several parks, including Mountwood Park, situated in the eastern section of the county adjacent to what was once the county's number one oil field boom town, Volcano, and within a mile of the county's highest point, which is 1,328 feet above sea level. Wood County has six islands, the largest of which is Blennerhassett, a part of the West Virginia state park system.

Within the county are some of the state's finest examples of Victorian Age architecture. There are five National Register historic districts and dozens of individual National Register historic properties.

The county's weather is generally moderate. However, on July 18, 1889, more than 19 inches of rain fell on Limestone Hill, at the southern tip of the county, in about two hours. Devastating floods hit the county almost annually before the completion of a floodwall in Parkersburg in 1950 and the construction of locks and dams on the Ohio, including one at Belleville.

Wood County has been the home of many prominent personalities. Among them are capitalists Johnson Newlon Camden, John M. Crawford, Monroe Jackson Rathbone Jr., Bernard Patrick McDonough, and Charlie O. Erickson; three governors between 1868 and 1900; U.S. diplomat William Kahn Leonhart; Admiral Felix Budwell Stump; pro-football hall of famer Alfred Earle "Greasy" Neale; college football hall of famer Floyd Schwartzwalder; the first bishop of the Episcopal Diocese of West Virginia, George William Peterkin; educator Waitman T. Barbe; entomologist Andrew Delmar Hopkins; and steamboat captain Anton Meldahl.