It begins in West Glendive at a Business Loop of Interstate 94 (I-94), and ends at the Port of Raymond on the Saskatchewan border.

The northern portion from U.S. Route 2 (US 2) at Culbertson to the Canada–United States border is proposed as part of the Theodore Roosevelt Expressway.

Leaving the Yellowstone Valley, MT 16 heads cross-country towards Culbertson, crossing the Missouri River a few miles south of town and entering Roosevelt County there.

In Culbertson itself, the road meets US 2, then leaves north, passing Froid's western outskirts and then crossing into Sheridan County.

It then has a clear run to the Canada–US border, continuing on as Saskatchewan Highway 6, connecting to Regina and beyond to Saskatoon.