From the southern border to Hope Mills, it runs very close to I-95, crossing it several times and having a short concurrency with the freeway in Lumberton.

From Hope Mills to Eastover, North Carolina it follows Interstate 95 Business, a partial freeway that passes through the center of Fayetteville.

Passing through towns such as Dunn, Benson, Smithfield, and Selma that are bypassed by I-95, numerous local businesses targeted at I-95 travellers line this stretch, rarely does it veer more than a fraction of a mile from I-95.

At Kenly, it leaves its close parallel of I-95, taking a route approximately 5 miles east of I-95 and passing through the center of the cities of Wilson and Rocky Mount.

North of Lumberton, it crosses I-95 twice before entering Fayetteville, overlapped with I-95 Business along Eastern Boulevard.

By 1958, US 301 was widen to a four-lane road around Lumberton, Fayetteville, and between Kenly and Rocky Mount; it was also at this time that Elm City was bypassed.

[2] From 1978 to 1986, US 301 was overlapped by a second I-95 Business Loop between Kenly and Rocky Mount, which also used part of what is today an extension of NC 4.