[1] Formed by the confluence of the Bettles and Dietrich rivers near Wiseman on the southern flank of the Brooks Range, the Middle Fork flows generally southwest to its confluence with the North Fork Koyukuk River, with which it forms the main stem of the Koyukuk.

[1][4] From its starting point slightly north of Sukakpak Mountain, the river flows generally south or southwest in its upper reaches.

[5] The Middle Fork is suitable for boating by a wide variety of watercraft for its entire length.

Chartered planes can land at Dietrich, near the head of the Middle Fork, and regularly scheduled flights serve Wiseman and Coldfoot.

Further downstream along the main stem of the Koyukuk River, scheduled flights serve Bettles and Allakaket.