US 378 connects the Central Savannah River Area in both states with the Midlands and Pee Dee regions of South Carolina.
US 378 is a major suburban and urban highway through Lexington and South Carolina's state capital, Columbia.
The highways pass along the west side of downtown Lincolnton and curve northeast, meeting the southern end of SR 79 (Goshen Street) before leaving the city.
SR 43 reaches its northern terminus at the state line at the thalweg of the Savannah River in the center of the lake crossing.
[8][9] US 378 enters Sumter National Forest and crosses the Little River branch of the lake, on the east side of which is Baker Creek State Park.
East of Liberty Hill, where the highway fully enters the national forest, the road crosses the McCormick–Edgefield county line.
The highway also intersects US 25 and SC 430 (Meeting Street Road) while passing along the northern tier of Edgefield County.
Two blocks to the east, US 378 turns north onto Jennings Street, then turns east on Travis Avenue at its junction with SC 194, which heads north on Jennings Street, and US 178 Connector, which heads west on Travis Avenue to connect with US 178.
After US 1 splits southeast to head to the center of town, US 378 continues on Columbia Avenue, then has a brief concurrency with SC 6 along Lake Drive.
The highway has a partial interchange with SC 12 (Jarvis Klapman Boulevard) that only allows access to and from Columbia.
Highways cross the Congaree River on the four-lane Gervais Street Bridge into Richland County and the city of Columbia.
At the intersection with SC 48 (Assembly Street), the highways pass between the South Carolina State House and Capitol Center.
Highways continue east along Devine Street to their intersection with SC 16 (Beltline Boulevard), where the road expands to six lanes.
US 378 and US 76 enter a rural area and pass through Horrell Hill, where they meet the northern end of SC 769 (Congaree Road), pass McEntire Joint National Guard Base, and have a junction with the western end of SC 764 (Old Eastover Road).
[8][10] East of the extensive swamp surrounding the Wateree River, US 378 and US 76 pass south of the village of Stateburg and intersect SC 261 (Kings Highway).
East of the base, the highways pass through a commercial area and meet the northern end of SC 120 (Alice Drive) just west of where Broad Street continues along US 76 Business while the U.S.
US 378 and US 76 cross a rail spur before highways exit the city of Sumter and the frontage roads reappear along the freeway.
The highway crosses the Black River and intersects SC 527 (Brick Church Road) at McBrides Corner.
US 378 has an acute junction with SC 53 (Narrow Paved Road) and a diamond interchange with I-95 before entering Clarendon County, where the route follows Clarence Coker Highway.
Highways split near the northern end of town, with US 378 continuing east as a four-lane road with center turn lane.
US 378 crosses over CSX's Charleston Subdivision before collecting the eastern end of US 378 Business (Myrtle Beach Highway).
The U.S. Highway meets the southern end of SC 908 south of Brittons Neck before it curves east and crosses the Little Pee Dee River into Horry County.
US 378 expands to a four-lane road with center turn lane shortly after passing Conway-Horry County Airport and enters the city of Conway as Wright Boulevard.
[8][10] In the early part of the 21st century, the bridge crossing the Georgia–South Carolina state line over the Savannah River was deemed to be "structurally deficient".
leaves the city limits at its crossing of Lake Swamp and reaches its eastern terminus at US 378 (Myrtle Beach Highway).
It directs truck traffic onto US 501, South Carolina Highway 544 Connector (Red Hill 1) (SC 544 Conn.), US 501 Business (US 501 Bus.
It is loosely signed, frequently in Conway and Red Hill, and infrequently outside the city limits of both locales.