In North Carolina, it is one of the main north-south corridors connecting the cities of Salisbury, Mocksville, and Mount Airy.

After crossing the north–South Carolina border, US 601 intersects with such highways as US 74 in Monroe, which it shares a short concurrency with until the interchange with the northern terminus of NC 207.

In Mocksville, the road has a short concurrency with US 64 beginning at the western terminus of US 158, and after leaving that overlap encounters Interstate 40 at exit 170.

Further north it has an interchange with US 421 in Yadkinville, Interstate 74 at exit 11 near White Plains, and finally terminates at US 52 in Mount Airy.

In 1965, US 601 was realigned on new road bypassing west of downtown Concord, leaving a business loop.

[1] In 1970, US 601 was realigned on new road bypassing east of Dobson, leaving a business loop.

[2] 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 July 1936, it was extended north to the Kershaw County line, east of Fort Jackson.

In November of that year, its path from the Eastover area to Lugoff was re-routed on new roadway.