Seneca Creek lies within the Appalachian Mountains, in the Spruce Knob-Seneca Rocks National Recreation Area of the Monongahela National Forest. It is formed by two spring-fed streams, Slab Camp Run and Trussel Run, on the western flanks of Spruce Mountain to the north of Spruce Knob. It empties into the North Fork of the South Branch at the community of Seneca Rocks near the base of the Seneca Rocks sandstone cliff formation.