MS 322 begins in the unincorporated community of Sherard at MS 1. The highway heads due east and enters the city limits of Clarksdale, but travels to the west and south of the downtown area. In the city, it carries the name Sherard Road. Within the city, MS 322 travels mostly past commercial and light industrial businesses. At
MS 161, MS 322 turns to the southwest to form a
concurrency with it for just over . At the southwest corner of Clarksdale, MS 161 ends at an intersection with
U.S. Route 61 (US 61) and
US 278 however MS 322 continues along US 61 and US 278 along its freeway bypass of Clarksdale. MS 322 exits the freeway at the interchange with
US 49 and then runs concurrent with it to the southeast for about in the community of Hopson. An independent route again, the roadway heads east through agricultural fields and leaves Coahoma County for Quitman County.{{Cite report |author=Mississippi Department of Transportation Planning Division |date=2019 |title=Mississippi Public Roads Selected Statistics Extent, Travel, and Designation ==Major intersections==