This route follows the Great River Road, a designated road route that follows the Mississippi River from source to sea. The route begins at the Mississippi headwaters in Lake Itasca, Minnesota and continues 2,000 miles south to Venice, Louisiana where the river meets the Gulf of Mexico.

The route crosses ten states — Minnesota, Wisconsin, Iowa, Illinois, Missouri, Kentucky, Tennessee, Arkansas, Mississippi, and Louisiana. Although the net elevation loss is only 1,475ft, the runner will climb about 50,000ft while following the river's twists and turns, banks, and bluffs.