The river's name is thought to be derived from Ganaraske, the Cayuga name for the village this Iroquoian nation had established in this area in 1779.

Together with other nations of the Iroquois Confederacy, they had migrated from New York, forced to cede their homelands because of having allied with the British in the American Revolutionary War.

The Crown provided additional lands to the Iroquois peoples, including what is now called the Six Nations of the Grand River reserve.

Later the Crown granted land here to United Empire Loyalists, in compensation for their losses in the Northeast colonies, especially New York.

The river had a flood in 1980, that caused considerable damage to the Port Hope downtown area.