The main branch flows generally east, flowing south of Lawrence. It joins the Kansas in Douglas County at Eudora, approximately 8 mi east of Lawrence. It is impounded by Clinton Dam approximately 3 mi southwest of Lawrence to form Clinton Lake.
The river is known for its gentle current that winds through river-level outcropping rocks, primary of Pennsylvanian limestone. This reach of the river was inhabited by different Native American tribes, including the Kansa and Osage Nation in the 18th century. During 1819-1820, Major Stephen H. Long referred to this tributary as "Warreruza." The name "Wakarusa" is derived from the Potawatomi language for "knee deep in mud."
After the U.S. acquired this region, the Shawnee people were relocated to this region during the early 19th century. Ridgelines of this historic watershed defined wagon train routes first used by Santa Fe Trail pioneers and Oregon Trail emigrants. During the Great Migration of 1843, the fords used for crossing this meandering river were among the many topographic challenges emigrant wagon trains had to master along the Fremont-Westport Trail (1843-1848) named after John C. Frémont. This Freedom's Frontier route also was called the California Road during the 1849 gold rush.
Also, during the days of the Kansas Territory, the limestone outcroppings of the river presented great challenges to early white emigrants attempting to ford the stream in their wagons. Oregon Trail wagons were often dismantled, lowered down the limestone beds, towed across, then lifted by rope to the opposing bank. Several Shawnee created ferry operations at river crossings in the 1850s, including Blue Jacket's Ferry near Coal Creek at Sebastian. The river's gentle current and scenic banks made it an early recreation spot for citizens of Lawrence (which was originally called "Wacharusa").
The river once had extensive wetland riparian habitat, much of which has been reclaimed over the last century for cultivation and other uses. Clinton Dam, finished in 1977 to reduce seasonal spring flooding, greatly reduced the replenishment of wetlands below the dam. A remaining tract of 600 acres), the Haskell-Baker Wetlands, is located south of Lawrence near Haskell Indian Nations University.
Though the wetlands below the dam are mostly dry now, along the Wakarusa above Clinton Lake, former cropland has been converted into a new wetland area. By pumping water into shallow ditches, 3 major manmade wetlands have formed, including the East and West Coblentz marshes, and the more recent Elk Creek wetland add more than 500 acres of wetlands along the Wakarusa River. The East and West Coblentz complexes are more accessible than the Elk Creek complex, and boast a large variety of waterfowl and reptiles. Due to the wetlands lying within the low Clinton Lake floodpool, access is very limited during the wet spring months.