The highway parallels US 51 during its trek roughly through the center of the Magnolia State.

North of Jackson, the Interstate runs east of the bluffs of the Mississippi Delta.

Near Summit and McComb, the Interstate is concurrent with US 98 for five miles (8.0 km) as it passes through the western side of the cities.

I-55 continues north on the eastern side of Jackson and meets the northern terminus of I-220 near Ridgeland.

The highway crosses the state line north of Southaven into Tennessee.