U.S. Route 601 is a north–south United States highway that runs for 316.3 miles (509.0 km) from U.S. Route 321, near Tarboro, South Carolina, to U.S. Route 52, in Mount Airy, North Carolina.

US 601 begins at US 321 near Tarboro, SC and intersects with such highways as US 278 in Hampton, US 301 between Bamberg and Orangeburg, US 78 in Bamberg, Interstate 26 near Orangeburg Interstate 20 near Lugoff, US 1 in Camden, US 521 between Camden and Kershaw, and SC 9 in Pageland.

After crossing the north–South Carolina border, US 601 intersects with such highways as US 74 in Monroe, NC 24/NC 27 in Midland, NC 49 south of Concord, Interstate 85 near Salisbury, Interstate 40 near Mocksville, US 421 in Yadkinville, Interstate 74 near White Plains, and US 52 in Mount Airy.

Established in 1927 as an original US Highway; the original routing was from US 1, in Cheraw, to US 17/US 76, in Florence.

In 1932, US 601 was extended north into North Carolina, replacing SC 96. In North Carolina US 601 was placed on concurrency with almost all of NC 80, from the South Carolina state line, near McFarlan, to downtown Mount Airy. In 1934, NC 80 was expunged from US 601.

In 1935, most of US 601 was replaced by the arrival of US 52. From Salisbury, North Carolina to Florence, South Carolina, the route was converted to US 52; which marked its departure from South Carolina.

Around 1952, US 601 was extended south from Salisbury. Starting with a concurrency with US 29 to Kannapolis, from there it followed US 29A to downtown Concord. Replacing NC 151, it continues south through Monroe and to the state line. In South Carolina, US 601 returns by replacing SC 151 from the border to Pageland. From there it replaced SC 902 and part of SC 265 to Kershaw. Between Kershaw and Camden, it overlaps with US 521. Replacing SC 26 from Camden to Orangeburg, then in concurrency with US 301 to Bamberg. Then finally replacing SC 36 to US 321, where it continues and ends with US 321 in Hardeeville.

In 1965, US 601 was realigned on new road bypassing west of downtown Concord, leaving a business loop. In 1970, US 601 was realigned on new road bypassing east of Dobson, leaving a business loop. In 1974, US 601 was extended to Interstate 95 in Hardeeville; however, by 1977, US 601 was truncated to its current southern terminus at US 321, near Tarboro. In 1979, US 601 was rerouted west of Salisbury, with concurrency with US 70; Innis Street was downgraded to secondary status. In the late 1980s, US 601 was rerouted onto Interstate 85, in Salisbury from exit 68 to exit 74; which was extended in the late 1990s, going south to exit 56 in Concord.

In 1999, US 601 was truncated to its current northern terminus at US 52 in Mount Airy.

U.S. Route 601 Truck is an alternate route for trucks to avoid downtown Orangeburg. The route overlaps with SC 4 on Stonewall Jackson Boulevard, then with US 21/US 178 on Joe S. Jeffords Highway/Whittaker Parkway/Chestnut Street.

U.S. Route 601 Truck is an alternate route for trucks to avoid downtown Camden. The route is in complete concurrency with US 521 Truck on Springdale Drive/Boykin Road.

U.S. Route 601 Business is a business loop that follows the original mainline of US 601 along Hampton Street. The route is in complete concurrency with US 521 Business.

The entire route is in Kershaw, Lancaster County.

U.S. Route 601 Business was established on October 1965 and followed the original route through downtown Concord, via Church and Union Streets and in concurrency with NC 73. On July 1997, the business loop was decommissioned

U.S. Route 601 Business, established in 1970, is a 4.1-mile (6.6 km) business loop that follows the original mainline route through downtown Dobson, via Main Street.

The entire route is in Surry County.