Mississippi Highway 6 runs east–west from MS 161 in Lyon, east to MS 25 near Amory. It travels approximately 136 miles (219 km), serving Coahoma, Quitman, Panola, Lafayette, Pontotoc, Lee, and Monroe Counties. West of Tupelo, it is concurrent with US 278.

On September 4, 2004, a 19 year-old University of Mississippi student named Dustin Dill from Orlando, Florida struck and killed a fellow student, 23 year-old pharmacy major and Oxford native Amie Ewing (who was also intoxicated), on this highway. Dill had a 0.12 percent blood-alcohol level when his Honda Accord struck Ewing and sent her into a parked Oldsmobile Achieva. 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.

Mississippi state and Oxford city laws prohibit the use of state highway shoulders as parking lots; however, this law went unenforced in Oxford on Saturdays when the Rebels played home games. Since this event, the 'no parking' laws along this highway have been enforced. This highway is now also known as "Amie Ewing Memorial Highway".

From east to west

From east to west