Beginning from the Georgia state line at the Savannah River, US 17 enters South Carolina in Jasper County, where it intersects with Interstate 95 (I-95).

It merges with I-95 until Point South, then heads east into Beaufort County, through the ACE Basin, and eventually reaches Charleston.

This historic road stretched from Charleston to Boston, Massachusetts, serving the major colonial cities along the Eastern Seaboard.

At Point South, US 17 leaves I-95 at exit 33 and heads eastward into northern Beaufort County, sharing a concurrency with US 21 until Gardens Corner.

[8] Once in Jacksonboro, the road enters into Charleston County crossing over the Edisto River and regaining a four-lane configuration for the remainder of the state.

Just before the interchange with I-526, major commercial development starts and continues into the West Ashley neighborhood of Charleston.

Upon reaching the eastern terminus of I-26, US 17 becomes controlled-access and above grade as it approaches the Cooper River via the Arthur Ravenel Jr. Bridge and the stretch of US 17 in Charleston is infamous among locals for its traffic congestion, especially on weekday mornings.

Upon crossing the river, the highway enters Mount Pleasant at grade and is signalized for several miles up through the second interchange with I-526 and connecting roads to the Isle of Palms and Sullivan's Island.

The road leaves the Charleston metropolitan area by entering the Francis Marion National Forest and going through the rural communities of Awendaw and McClellanville on its northeastern journey to Georgetown.

After going through Georgetown, US 17 crosses eastward over the Waccamaw–Pee Dee river system before making a northward turn along the Grand Strand.

[8] The last component of US 17 runs close to the Atlantic Ocean, beginning at Hobcaw Barony and DeBordieu Colony, passing by Pawleys Island, and going past the Litchfield beaches and Murrells Inlet.

[8] The portions from Murrells Inlet to the state line are quite congested at times, though the soon to be constructed I-73 should assist in alleviating many traffic issues.

[12] The early routing was already identified to be shifted to the King's Highway which would pass through Myrtle Beach and Georgetown; rerouting occurred in 1935.

The divided section in Coosawhatchie remains intact, while the northbound lane near the Tullifinny wetlands was closed, and today is used for a fishing pier, a parking lot of a church, and a private home.

[citation needed] In 1997, US 17 was rerouted to cross the Georgia state line through Savannah, this new segment replaced US 17 Alt.

[21] In 1985, the South Carolina Department of Transportation (SCDOT) recognized the need to improve the segment of US 17 due to substantial capacity and safety concerns.

[29] A section from 8th Avenue North to Starwatch Drive in Horry County is named the George Rayford Vereen Highway.

[30] A section from Old Jacksonboro Road to South Carolina Highway 7 (SC 7) is named the Curtis B. Inabinett, Sr.