[5] The headwaters of the river rise under Devils Thumb on the Mount Carbine Tableland in the Great Dividing Range.

The river flows through a deeply incised valley in the Mount Lewis Forest Reserve in an easterly direction and then through the Mossman Gorge, part of the Daintree National Park,[6] and onto the coastal plain past the township of Mossman, where the river is crossed by the Captain Cook Highway.

The river eventually discharges into Trinity Bay and the Coral Sea between Newell and Cooya Beach.

The traditional language region is Mossman River in the south to the Annan River in the north, bordered by the Pacific Ocean in the east and extending inland to west of Mount Mulgrave.

[9] The river was named by the explorer George Dalrymple in 1873 after Hugh Mosman who discovered gold in Charters Towers.