It is the main highway for the towns of Deloraine (where it meets PTH 3), Hartney, Hamiota, and Shoal Lake.

Traveling along the western edge of Turtle Mountain, the highway heads north, running along the border with the Rural Municipality of Brenda - Waskada, to have a junction with PR 251 before bypassing the town of Deloraine along its western side, where it has a short concurrency (overlap) with PTH 3 (Boundary Commission Trail), crossing a small creek.

The highway enters the Rural Municipality of Hamiota, passing by Oakner on its way to Parks Corner, where it junctions with PTH 24.

[4] Provincial Road 455 (PR 455) is a 11.6-kilometre-long (7.2 mi) east-west spur of PTH 21 in the Rural Municipality of Whitehead, providing access to the town of Alexander.

It is entirely a two-lane road, with the segment in the town of Hamiota, also known as Birch Avenue, being paved, while the rest is gravel.

Provincial Road 541 (PR 541) is a 6.5-kilometre-long (4.0 mi) east-west spur of PTH 21 in the Municipality of Grassland, providing access to the hamlet of Grande-Clairière.

Provincial Road 543 (PR 543) is a 11.5-kilometre-long (7.1 mi) east-west spur of PTH 21 in the Rural Municipality of Sifton, providing access to the hamlet of Oak Lake Beach.

It is entirely a two-lane gravel road, with no other major intersections or settlements to speak of as it travels through a mix of rural farmland and wooded areas.