With the exception of a break at the Tennessee-Tombigbee Waterway in Fulton, MS 178 is a complete route from Memphis, Tennessee, to the Alabama state line.

MS 178 begins at the Tennessee state line in DeSoto County, with the road continuing northwest into the city of Memphis as Old Highway 78.

MS 178 crosses a bridge over the Coldwater River as it passes through woodlands before entering Marshall County.

It leaves downtown and has an intersection with MS 703 before leaving Byhalia and traveling southeast through a mix of farmland and wooded areas for the next several miles, passing through the communities of Victoria and Red Banks, before entering the town of Holly Springs at an interchange with Landfill Road, the new Holly Springs bypass.

The highway passes neighborhoods, and then a large and long business district, before crossing the Tallahatchie River into downtown.

The highway winds its way east through the hilly terrain of the North Central Hills for the next several miles, passing through the town of Tremont (where it has a short concurrency with MS 23, before coming to another dead end at the Alabama state line.

In the 1980s US 78 began to be upgraded further, albeit in stages, into a four-lane, interstate-style route, bypassing parts of the original 1940s US 78 alignment.