It runs in a south-westerly direction through deep valleys for approximately 340 kilometres (211 mi), passing through the Waterloo Ranges before descending to the coastal plain.

The lower reaches of the Greenough are estuarine; how far upriver the estuary extends is not certain, but probably about 7 km to near Bootenal Springs.

[4] Evidence from wind gaps suggests that, thousands of years ago, the Greenough River turned to the north-west a few kilometres further from the coast than it does at present, at the present-day site of Walkaway.

However, the entire basin is prone to severe flooding which has periodically devastated local farming communities.

[5] The river water is eutrophic and sediment-laden, and there is evidence that this has affected the ecology of the area, with migratory wading birds no longer visiting the floodplain in numbers as large as previously.