While exploring the Little Kanawha River Valley in 1772, frontiersman Jesse Hughes discovered a major tributary and named it in honor of himself. He had previously dubbed a creek in Lewis County Jesse Run. In 1789, Hughes's detractors attempted to have Hughes River renamed "Junius River," in honor of an 18th-century British writer, but their effort failed.

The Hughes River drains Ritchie County and part of Wirt in West Virginia. It empties into the Little Kanawha River at the Wood-Wirt county line, 18 miles east of Parkersburg. At this convergence, Hughes River is 600 feet above sea level. About 12 miles upstream from its mouth, Hughes River divides into the North and South forks near the town of Cisco in Ritchie County. Harrisville, the county seat of Ritchie County, is located on the North Fork of Hughes.

The North Fork of Hughes River has its headwaters at the Ritchie-Tyler county line, near the community of Mountain, and it is 57 miles long. The South Fork is 54 miles long. It rises in southwestern Doddridge County, near the community of Porto Rico, and flows through southern Ritchie County to join the North Fork. Hughes River's chief tributary is 28-milelong Goose Creek, which forms a part of the border between Wood and Ritchie counties. Goose Creek flows into Hughes River at the town of Freeport in Wirt County.

Geologically, the forks of the Hughes have eroded deep channels into the massive strata of the Waynesburg Sandstone, creating a rough topography, with steep sandstone cliffs and narrow valleys. Hughes River contains a variety of fish, including muskie; spotted, small mouth and rock bass; flathead and channel catfish; and several species of sunfish. The Hughes River Wildlife Management Area, a popular hunting area, straddles the river northeast of Elizabeth.