Parkersburg is situated at the confluence of the Little Kanawha and Ohio rivers. With the formation of Wood County from Harrison County in 1799, the settlement (by then known as Newport) was made the county seat. In 1800, the Virginia Assembly granted a charter for Newport, on the north side of the Little Kanawha, and for Monroe, on the south side. Ten years later, Newport was rechartered and renamed for Capt. Alexander Parker, of Carlisle, Pennsylvania, who had bought the property in 1785.

In 1795, Harman and Margaret Blennerhassett purchased what had previously been called Backus Island, two miles below Parkersburg. Aaron Burr, gaining the Blennerhassetts' trust in 1804, made Blennerhassett Island a rendezvous for his disastrous proposed expedition to Spanish-held lands in the southwest. Today, the Blennerhassetts' island mansion, grandly replicated, is a major tourist attraction and centerpiece for a state historic park.

Riverboat transportation grew in importance during the first half of the 19th century. The completion of the Northwestern Turnpike into Parkersburg in 1838, the Staunton-Parkersburg Turnpike in 1847, and the Northwestern Virginia Railroad in 1857, brought important land links to the Ohio River at Parkersburg. New development followed.

During the Civil War, 3,000 Wood Countians, many from Parkersburg, served in the U.S. Army and approximately 200 in the Confederate. In 1861-62, Parkersburg residents Dr. John W. Moss, Peter Godwin Van Winkle, Arthur Ingraham Boreman, and Jacob Beeson Blair were among the founders of the unionist Reorganized Government of Virginia, which led to the creation of West Virginia. Boreman was the first governor of West Virginia and served three successive terms. Van Winkle served one term in the U.S. Senate. Joseph H. Diss Debar of Parkersburg was called upon to design the West Virginia state seal. By the early 20th century, Parkersburg had supplied three more governors: William Erskine Stevenson, Jacob Beeson Jackson and Albert Blakeslee White.

In 1861 and after, Parkersburg found itself the center of a booming oil industry, surrounded by major oil fields at Burning Springs, Wirt County; Volcano, Wood County; and elsewhere. Johnson Newlon Camden established one of the country's first oil refineries in Parkersburg in 1869, which he secretly sold out to Standard Oil in 1875 but continued to operate. In doing so, he helped John D. Rockefeller’s company establish near total control over the oil industry. Camden later was two times elected a U.S. senator.

Sumner School, the first school for Black children in West Virginia, was established as a subscription school in Parkersburg in 1862. It became part of the segregated public school system in 1866.

Mountain State Business College was founded in 1888; Ohio Valley College in 1960; and in 1961, the Parkersburg Branch of West Virginia University was first located on Emerson Avenue and later moved to Cedar Grove.

The Parkersburg Rig and Reel Company, an oil field service company, was for 70 years one of the city's chief employers. The O. Ames Company, the world's largest manufacturer of shovels, arrived in the early 1930s. The American Viscose Corporation started rayon production in South Parkersburg in 1927, closing in 1974. A major DuPont plant was built at Washington Bottom in 1949, followed by Marbon Chemical (G.E. Plastics today) in 1957.

With manufacturing booming, Parkersburg’s population increased steadily during the first half of the 20th century but began declining as factories closed. It reached a peak of 44,797 people in 1960 and decreased significantly in the 1970s. In 2020, the population was 29,749, making it the fourth largest city in West Virginia, trailing Charleston, Huntington, and Morgantown.

Mid-Ohio Valley Regional Airport, which began offering flights in 1946, is located seven miles northeast of the city.