The river rises on the slopes of the Great Dividing Range within the Daintree National Park below Kalkajaka at an elevation of 1,270 metres (4,170 ft) AHD.

The river is joined by two minor tributaries before flowing through the Cairns Marine Park through thick mangrove swamps where the water is highly saline; and then empties into the Coral Sea, north of Wonga Beach.

Combined with the climatic conditions of the area the river is prone to quickly developing floods with little warning due to the high rainfalls on the 1,000-metre-high (3,300 ft) mountain ranges around the catchment and the influence of the cyclonic forces in the adjacent Coral Sea.

[9] The Wet Tropics of Queensland was given UNESCO World Heritage listing, inclusive of the Daintree River in recognition of "its outstanding natural universal value as an outstanding example representing; the major stages of Earth's evolutionary history, significant ongoing ecological and biological processes, superlative natural phenomena and as containing important and significant habitats for in situ conservation of biological diversity.

This pine-like tree is the only remaining species in the Gymnostoma group of plants in Australia, and is now restricted to very isolated pockets north of the Daintree River.

Once considered a light-coloured form of the Herbert River ringtail possum, commonly found throughout the Atherton Tablelands, it was described as a distinct species in 1989.

Black and white Striped possums (Dactylopsila trivirgata) are quite common throughout the park, particularly in the coastal lowlands north of the Daintree River, although to see one while spotlighting requires a mixture of luck and know-how.

[10][11][12] Authorities warn tourists and visitors not to step close to the riverbank, and stay within the confines of boats, and absolutely never swim in the river.