As are most other US numbered highways in the state, this entire section of US 82 is defined in Mississippi Code Annotated § 65-3-3.

After crossing the Mississippi River from Arkansas via the four-laned, cable-stayed Greenville Bridge, the road briefly travels northeast toward central Greenville, then turns east toward Leland, where it intersects US 61, as US 278 breaks it concurrency and goes on to follow US 61 north.

From Starkville east through Columbus up until the Alabama state line, US 82 is built to freeway standards.

It forms a brief concurrency with US 45 in Columbus, as both highways cross the Tennessee-Tombigbee Waterway together via an unnamed bridge.

As US 45 heads north, US 82 continues to wind its way around the city, finally crossing into Alabama almost immediately after an interchange with Lee Stokes Road.