MS 12 traverses three major regions of the state, the Mississippi Delta, the North Central Hills, and the Golden Triangle.

The highway now leaves Hollandale and continues east through rural farmland for several miles to cross the Sunflower River into Humphreys County.

The highway continues east through rural farmland and woodlands for several miles to enter Holmes County.

MS 12 crosses Tchula Lake before traveling along the southern edge of Marcella and coming to an intersection and becoming concurrent with US 49E.

It crosses another creek before leaving Lexington and traveling through some farmland and wooded areas for several miles, where it passes through Owen Wells, to have an interchange with I-55 (Exit 156) and entering Durant.

MS 12 heads southeast through a business district before turning south along US 51 (N Jackson Street) through neighborhoods into downtown.

MS 12 now leaves Ackerman and winds its way east through remote, hilly, and wooded terrain for the next several miles to cross into Oktibbeha County.