The eastern terminus is at ND 6 about 5 miles (8.0 km) north of Breien and the western terminus is at U.S. Route 85 (US 85) about 5 miles (8.0 km) east-northeast of Amidon.

The highway is known for the large number of abandonments located along it.

ND 21 runs east from its western terminus at US 85 for 15.7 miles before turning south onto ND 22 near New England for 8.1 miles.

after the concurrency, ND 21 heads east for 28.7 miles, intersecting the Enchanted Highway and passing south of Regent, and sharing the road with ND 8 near Mott.

In Mott, ND 21 turns off again to head east for the last 69.5 miles; along the way, ND 21 skirts north of Burt, picks up ND 49 near New Leipzig and exits the concurrency at Elgin, passes north of Heil and south of Carson, and meets the northern end of ND 31 near Flasher.