MS 338 begins at an intersection with US 278/MS 6 about three miles (4.8 km) southeast of the town of Thaxton.

It heads east through farmland for a few miles to enter the city of Pontotoc along West Oxford Street.

MS 338 travels through more neighborhoods before leaving Pontotoc and winding its way through hilly woodlands for a couple of miles to come to an end at an interchange with US 278/MS 6 near Trace State Park.

MS 338 was designated and signed in 2007 when US 278/MS 6 was realigned onto the new northern bypass of Pontotoc, the Pontotoc Parkway, which until that time was signed as MS 76 (part of Corridor V of the Appalachian Development Highway System).

The original routing of MS 338 was a short-lived (between 1960 and 1962) state highway designation for Antioch Road in western Pontotoc County, Mississippi.