The river rises in the Grampian Ranges and flows generally north, then west, then south, for over 350 kilometres (220 mi),[10] making the river the longest river in south-west Victoria and third longest overall. A short stretch of the lower end winds through southeastern South Australia before returning to Victoria to enter Discovery Bay at Nelson. The Glenelg River is a central feature of the Lower Glenelg National Park.
Large amounts of water diverted from the upper reaches of the river for agricultural purposes, including irrigation and town water demands. The estuary is listed under the Heritage Rivers Act, 1992 (VIC) and is a nationally important wetland.