Route 181 begins at an intersection with US 160 near Gainesville and heads northeast, intersecting Route 80. The route passes by Caney Mountain Conservation Area before passing through Zanoni and crossing over Pine Creek. It then passes through Sycamore, past the Hodgson Mill and continues northeast. It then heads due north through Dora in Ozark County and meets Route 14. The route then runs concurrent with Route 14 for 4.8 miles (7.7 km) until meeting the twin bridges at the North Fork River and Spring Creek.The two bridges on Route 14 are separated by an 880-foot-wide (270 m) low point in a north–south trending ridge between the North Fork River and its tributary Spring Creek to the east.^[2] Then, the route continues north until meeting up with Route 76 and runs concurrent with it for about 3.5 miles (5.6 km). It then continues north until it approaches Cabool. It interchanges with US 60 before crossing over the Big Piney River and reaching its northern terminus at US 60 Business.^[2]