It traverses approximately 235 miles (378 km), serving Hancock, Pearl River, Marion, Jefferson Davis, Lawrence, Simpson, Rankin, Madison, Leake, and Attala counties.

MS 43/MS 603 pass through the suburban community of Shoreline Park for the next several miles to cross Bayou La Croix and have an interchange with I-10 at Exit 13.

The heads northward through rural terrain for the next few miles, where it narrows to two-lanes and has an intersection with the access road for Stennis International Airport, which also houses many of the county's services.

The highway now parallels the Pearl River as it winds its way north through wooded areas for several miles to cross into Marion County, coming to an end shortly thereafter at an intersection with MS 13 between Columbia and Lumberton.

The highway continues northwest to have a short concurrency with MS 184, just across the Pearl River from Monticello, before joining US 84 east for a few miles.

The highway winds it way northeast as it parallels the Strong River for several miles before entering Mendenhall and immediately coming to an end at another intersection with MS 13 just west of downtown.

The highway heads north out of Kosciusko through remote terrain for several miles to the Montgomery County line, where MS 43 comes to an end at an intersection with Winfry Road.

The route is not legally defined in Mississippi Code § 65-3-3,[6] and is a county road and city street not maintained by MDOT.