It begins at State Routes 70 and 107 in southern Greene County and ends at State Route 93 in northern Greene County.

It goes northeast as State Route 107 cutoff, where it winds its way through farmland, running parallel to the Nolichucky River, to have an intersection with SR 350.

They pass through rural areas before SR 351 splits off at a y-intersection as Chuckey Pike.

It winds its way northwest through farmland before crossing a bridge over the Nolichucky River, where it leaves the river for good, before passing through Chuckey, where it has an intersection with US 11E/US 321/SR 34.

SR 351 continues northwest as Rheatown Road through rural areas before entering Newmansville and coming to an end at an intersection with SR 93.