Waynesboro is concentrated around the junction of State Route 13 and U.S. Route 64, 105 miles (169 km) south of Nashville, and 135 miles (217 km) east Memphis. State Route 99, which intersects US 64 in eastern Waynesboro, connects the city with Hohenwald to the northeast. The Natchez Trace Parkway intersects US 64 a few miles east of Waynesboro.

Waynesboro lies along the banks of the Green River, which slices a narrow valley oriented north-to-south en route to its mouth along the Buffalo River to the north. Hurricane Creek, which approaches from the southeast, empties into the Green River just north of the city. Much of the forest northwest of Waynesboro is part of the Eagle Creek Wildlife Management Area.