It travels approximately 139 miles (224 km), serving Coahoma, Quitman, Panola, Lafayette, Pontotoc, Lee, and Monroe Counties.

MS 6/US 278 now leave the Clarksdale area and pass through farmland for several miles, where it crosses the same bayou three times, before entering Quitman County.

The highway passes through some neighborhoods and business districts as it bypasses downtown along its southern side and has a concurrency with MS 35.

It widens to a four-lane undivided highway at an intersection with US 51, where MS 35 splits off, before passing through a major business district to come to an interchange with I-55 (Exit 243).

The highway now has an interchange and concurrency with MS 315, which splits off unsigned onto Black Jack Road, providing access to Sardis Lake and John W. Kyle State Park.

At this interchange, MS 6 splits off from US 278 and heads north along the US 45 freeway through the eastern side of the city of Tupelo for several miles.

They immediately cross Town Creek before entering some neighborhoods as a four-lane undivided highway, where MS 6 splits off and heads south along its own path near the Elvis Presley Birthplace.

Dill had a 0.12 percent blood-alcohol level when his Honda Accord struck Ewing and sent her into a parked Oldsmobile Achieva.

[3][4] Ewing had parked along the shoulder of Highway 6, then walked to Vaught–Hemingway Stadium to watch the Ole Miss Rebels football team play the University of Memphis Tigers and was killed when she crossed the westbound lane of the highway approximately 1,000 feet (300 m) east of Old Taylor Road while returning to her car.