MS 42 runs in an east/west direction for 116.0 miles (186.7 km), serving seven Mississippi counties: Wayne, Greene, Perry, Forrest, Lamar, Jefferson Davis, and Lawrence.

The highway immediately crosses a bridge over West Prong Silver Creek and it winds its way southeast through a mix of farmland and wooded areas for several miles to enter the town of Prentiss at an intersection with US 84.

It heads south along 3rd Street through neighborhoods, where it passes by Prentiss Elementary School, before making a right turn onto Columbia Avenue (Original US 84) at the Jefferson Davis County Courthouse.

The highway leaves Prentiss and travels southeast through woodlands for several miles, where it passes by Jeff Davis Lake, through the community of Carson, and through the town of Bassfield (where it has an intersection with MS 35).

MS 42 passes eastward through the community of Glendale before crossing a bridge over the Leaf River to enter the neighboring city of Petal.

The two highways head straight up the middle of downtown for several blocks before MS 42 splits off along Redbud Avenue to leave Richton and cross the wooded marshland surrounding Thompson Creek.

This resulted from the construction of the Evelyn Gandy Parkway, a new four-lane divided expressway that entirely bypasses the city along its northern side, running from I-59 (Exit 69) to the eastern edge of Petal.