U.S. 64 comprises the longest route within the state of North Carolina. Traveling over 600 miles, U.S. 64 crosses the state from the Tennessee state line to Nags Head on the Outer Banks. Entering North Carolina with U.S. 74, U.S. 64 ventures 16 miles from Isabella, Tennessee to Ranger. Just east of there U.S. 64/74 join U.S. 29/129 for a seven mile drive to the Cherokee County seat of Murphy.
U.S. 64 leaves U.S. 29-74-129 at Murphy to skim the southern reaches of Clay, Macon, Jackson and Transylvania Counties. This includes a 2009-realignment from Murphy east to North Carolina 141. The winding route travels to Hayesville, Chatuge Lake, Shooting Creek and Rainbow Springs on the route between Murphy and Franklin (U.S. 23/441). U.S. 64 merges briefly with U.S. 23/441 to bypass Franklin to the south. A U.S. 64 Business loop also serves Hayesville.
Once outside of Franklin, U.S. 64 reduces to two lanes and heads southeasterly again to Highlands along side North Carolina 28. North Carolina 28 departs there for Pine Mountain, Georgia as U.S. 64 turns back to the northeast to Cashiers, Sapphire and Cherryfield. U.S. 64 meets the northern terminus of U.S. 178 in central Transylvania County near the town of Rossman.
Nine miles separate U.S. 178 and the Transylvania County seat of Brevard along a four-lane divided stretch of U.S. 64. The highway, in conjunction with North Carolina 280, provides a direct route to Interstate 26 and the Asheville metropolitan area to the northeast. U.S. 64 joins U.S. 276 for a three-mile overlap between Downtown Brevard and North Carolina 280 before turning eastward to Etowah and Hendersonville. Through Brevard, a U.S. 64 Truck route follows Caldwell Street one block north of U.S. 64 (Broad Street). A longer U.S. 64 Truck follows U.S. 74 and Interstate 40 between Hendersonville and Murphy.