U.S. Route 278 runs in a northwest to southeast direction from the Georgia state line in North Augusta to Hilton Head Island on the Atlantic coast.

After crossing the Savannah River from Georgia, U.S. 278 bypasses downtown North Augusta, South Carolina to the south en route to Beech Island and Johnson Crossroads. It then forms a de facto northern boundary of the Savannah River Site, crossing into the property on a few occasions. The route then continues eastward and then southward through the communities of Barnwell, South Carolina, Kline, South Carolina, Allendale, Fairfax, Hampton, Varnville, Ridgeland, and Hardeeville where it meets I-95. U.S. 278 shares the route between Ridgeland and Hardeeville with U.S. 17. Prior to the construction of Exit 8 on Interstate 95 (which provides direct access to southern Beaufort County), U.S. 278 went from Ridgeland through Old House and Okatie along present-day state highways 336, 462, and 170.

Upon reaching Hardeeville, the route heads eastward toward the Atlantic with large residential and commercial developments lining the spine of the road from Hardeeville through Okatie and Bluffton. The route crosses over Calibogue Sound onto Hilton Head Island. After a five mile stretch in which the route is tolled, U.S. 278 ends at U.S. 278 Business on the southern portion of Hilton Head Island, just outside Sea Pines Plantation.

On Hilton Head Island, U.S. 278 was previously routed along what is now U.S. 278 Business until a new toll road, named the Cross Island Parkway opened on January 16, 1998. The 6.8 mile section of roadway cost $83 million to build and was was funded with a combination of state funds, federal funds, state highway bonds and tolls.

The controlled access toll road has only one interchange along its route at Marshland Drive. It was the first toll road built in South Carolina in modern history. A majority of the road users pay their tolls using Palmetto Pass, South Carolina's system for electronic toll collection. Tolls will be removed once the bonds sold to build the road are retired.

The completion of the Cross Island Parkway (a direct expressway connection from the north side to the south side of the island), has caused a great amount of commercial and residential development along the road.[citation needed] Before the toll road opened, it could take one hour to travel the 12-mile route of what was then signed as U.S. 278 (William Hilton Parkway) during peak tourism season. The Cross Island Parkway greatly relieved congestion on that road when it opened.