From its source near Wareham, Ontario, it flows south through Grand Valley, Fergus, Elora, Waterloo, Kitchener, Cambridge, Paris, Brantford, Ohsweken, Six Nations of the Grand River, Caledonia, and Cayuga before emptying into the north shore of Lake Erie south of Dunnville at Port Maitland.

The river's mostly rural character (even when flowing through the edges of Waterloo and Kitchener), ease of access and lack of portages make it a desirable canoeing location, especially the stretch between West Montrose and Paris.

The Grand Valley Dam, located near the village of Belwood, helps to control the flow of water, especially during periods of spring flooding.

The Laphroaig site (AgHa-54) on the lower Grand River shows evidence of occupation in the latter part of the Early Archaic period.

For example, the Canada Century site (located on the Welland River) lies 17 kilometres (11 mi) north of the Lake Erie shore, but may once have been significantly closer.

Tincombe points out, however, that fishing may still have occurred on the upper Grand River, notwithstanding a lack of surviving remains at sites.

[28] He further proposes areas around Caledonia and Brantford as persistent places of occupation in the Late Archaic, due to a high concentration of consecutively dated sites from that period.

Discovered in 1994, the site contains materials dating to the Early, Middle, and Late Archaic periods, as well as the later Princess Point complex.

[33] Indeed, early evidence of lake sturgeon fishing on the Grand River has been discovered at the Cayuga Bridge site, which is also associated with the Princess Point complex and dated to AD 700–900.

The Wyandot, another distinct Iroquoian-speaking nation, who resided northeast of the Grand River valley, had long competed to remain independent of their enemy the Iroquois Confederacy, a powerful alliance of five nations based around the Great Lakes in the present central and western New York state area.

The consensus is that the Seneca and the Mohawk nations of the Iroquois destroyed the smaller Neutral tribe in the 17th century, in the course of attacking and severely crippling the Huron/Wyandot.

Other descendants of the Neutrals may have joined the Mingo, a loose confederacy of peoples who moved west in the 1720s, fleeing lands invaded by Iroquois, and settled in present-day Ohio.

After the desolation of the Neutral tribe, the Iroquois Confederacy used the Grand River Valley as a hunting ground and trapping territory.

Though the Six Nations (by then including the Tuscarora) held the territory by right of conquest, they did not settle it, apart from a limited presence on the northern and western shores of Lake Ontario.

Warfare throughout the frontier of the Mohawk Valley had resulted in massacres and atrocities on both sides, aggravating anti-Iroquois feelings among the colonists.

Without consultation or giving the Iroquois a place in negotiations, the British ceded their land in New York to the new United States.

After the war, Six Nations leader Joseph Brant appealed to the British Crown for help, as they had promised aid for allies.

Throughout the 19th century, many Anglo-Canadian settlements developed along the Grand within former Six Nations territory, including Waterloo, Berlin (now Kitchener), Cambridge, Paris, Brantford, Caledonia, Dunnville and Port Maitland.

After the American War of Independence, the Crown purchased land from the Mississaugas in Upper Canada to award as grants to Loyalist refugees as compensation for their property losses in the colonies.

Loyalists from New York, New England and the South were settled in this area, as the Crown hoped they would create new towns and farms on the frontier.

This grant was confirmed, and its conditions defined, by a patent under the Great Seal, issued by Lieutenant Governor Simcoe, and bearing date January 14, 1793 ...

The original extent of the tract was 694,910 acres, but the greater part of this has been since surrendered to the Crown, in trust, to be sold for the benefit of these tribes.

And some smaller portions have been either granted in fee simple to purchasers with the assent of the Indians, or have been alienated by the chiefs upon leases; which, although legally invalid, the government did not at the time consider it equitable or expedient to cancel.