The river rises on the eastern slopes of Jerusalem Mountain within the Nightcap National Park, and flows generally southeast, west southwest, and south, joined by five minor tributaries, before reaching its mouth at its confluence with the Richmond River, near Coraki; descending 359 metres (1,178 ft) over its 131 kilometres (81 mi) course.

The traditional custodians of the land surrounding the Wilsons River are the Aboriginal people of the Bundjalung clan, who lived as hunter-gatherers.

[4] Because of the extensive development of the catchment for agricultural and urban purposes the river system is adversely impacted by inputs of sediments, nutrients, gross pollutants and other contaminants.

In the lower portion of the Wilsons River the declared noxious species European Carp is common.

One is the relatively high rainfall in the headwaters of the system (The Rummery Park Rain Gauge is the Wettest in NSW)[6] and the unusual geomorphology which means that the River flows away from the sea for a significant distance then south after reaching Lismore before joining the Richmond River which eventually flows north east to the Tasman Sea.

Additionally, the balance of the catchment is located near sea level reducing the hydraulic gradient and slowing the rate at which water can flow.

However, the high frequency of flooding limits its use mainly to pastures for cattle grazing and dairying enterprises.

Goods regularly transported early in the 20th century included bacon, maize, eggs, butter, tallow, poultry and sawn logs.

The confluence with Coopers Creek is near the village of Bexhill at Boat Harbour Nature Reserve which is one of the largest remnants of the Big Scrub rainforest.