Via the Ohio River, it is part of the watershed of the Mississippi River, draining an area of 357 square miles (920 km2) on the unglaciated portion of the Allegheny Plateau.

Symmes Creek rises in Bloomfield Township in southeastern Jackson County and flows generally southward through Madison Township in Jackson County; Greenfield, Perry, and Walnut townships in Gallia County; and Symmes, Aid, Mason, Lawrence, Windsor, and Union townships in Lawrence County, through a portion of the Ironton Unit of the Wayne National Forest and past the communities of Waterloo, Aid, and Willow Wood.

It joins the Ohio River at the village of Chesapeake, opposite downtown Huntington, West Virginia.

According to the Geographic Names Information System, it has also been known historically as "Simms," "Big Creek," and "Symms Creek.

"[1] At the United States Geological Survey's stream gauge in Aid, the annual mean flow of Symmes Creek between November 2000 and September 2005 was 426 ft³/s (12 m³/s).