It currently runs for 1,074 miles (1,728 km) from Hilton Head Island, South Carolina, to Wickes, Arkansas at US 71/US 59, passing through five states in the process.

Landmarks along its route include the Department of Energy's Savannah River Site in South Carolina and the Tennessee-Tombigbee Waterway in eastern Mississippi.

Entering Hempstead County, the highway winds through rural areas to Ozan and Washington, before meeting US 278 Business (US 278B) outside Hope.

Long-term plans are to move US 278 to the Charles W. Dean Bridge,[9] which is part of the proposed extension of I-69.

East of Clarksdale, it overlaps Mississippi Highway 6 through Batesville, Oxford, and Pontotoc before reaching Tupelo.

Prior to the completion of Corridor X (Future I-22), these two routes also overlapped US 78 between these two towns; eastbound US 78 traveled in the same direction as westbound US 278.

In Lithonia, Georgia, at the intersection with Turner Hill Road (SR 124), US 278 merges with I-20 for 15 miles (24 km).

In Atlanta, US 278 merges further with other highways including SR 10 and US 23 before splitting off at Ponce de Leon Ave. and East Lake Road near Decatur.

After crossing the Savannah River, US 278 bypasses North Augusta, South Carolina, en route to Beech Island and Johnson Crossroads.

The route then continues onward through the towns of Allendale, Fairfax, Hampton, Varnville, Ridgeland, and Hardeeville where it meets I-95.

Upon reaching Hardeeville, the route heads eastward toward the Atlantic with major new developments lining the spine of the road from Hardeeville through Sun City and Bluffton before crossing over the bridge to Hilton Head Island.

US 278 ends at US 278 Business on the southern portion of Hilton Head Island, just outside Sea Pines Plantation.

The extension was routed along US 43 from Guin to Hamilton, Alabama, then over SR 74 to the Georgia state line.

[16] The following year, the highway was relocated on Hilton Head Island, South Carolina; the former routing because US 278 Bus.