The river originates south of the Great Bear Lake.

The river turns south-west, where the Mink Lake is formed along its course.

Horn River then flows south, and it receives the waters of the Bluefish River before it empties into the Mackenzie River, 100 kilometres (62 mi) downstream from the Great Slave Lake), immediately upstream from Mills Lake, at an elevation of 150 metres (490 ft).

The arch made by the river defines the Horn Plateau, a flat elevated area that rises up to 820 metres (2,690 ft)) to the north and east, while the south is defined by the Mackenzie River east of Fort Simpson.

From origin to mouth, the Horn River receives: Download coordinates as: