It travels approximately 192 miles (309 km), serving DeSoto, Tunica, Tate, Panola, Quitman, Tallahatchie, Sunflower, Humphreys, Yazoo, and Warren counties.

It heads northeast, paralleling the river, as a two-lane highway for several miles along the western edge of a hilly plateau, which marks the eastern boundary of the Mississippi Delta, to cross into Yazoo County.

MS 3 now comes to an interchange with US 49W, which it becomes concurrent with and follows northward as a four-lane divided highway to pass through farmland for several miles, crossing over the Yazoo River, before entering Humphreys County just southwest of Carter.

US 49W/MS 3 continue northwest to pass through Isola, where it has an intersection with unsigned MS 806 (Belzoni Street) and crosses over Lake Dawson, before entering Sunflower County.

The highway passes northeast through rural areas for several miles before entering Tutwiler and US 49W comes to an end at a Y-Intersection/interchange between US 49 and US 49E, with MS 3 continuing north along US 49.

The highway now has a partial interchange with MS 304 before coming to an end shortly thereafter at an intersection with US 61 along the south side of the community of Lake Cormorant.