The river proper flows from the eastern end of Eleven Mile Lake in Annapolis County southward to Kejimkujik Lake in Kejimkujik National Park, then through Lake Rossignol to empty into the Atlantic Ocean at the town of Liverpool, Nova Scotia.

The true source of the river however is as far northwest as Sandy Bottom Lake (Annapolis County) or Tuskopeake Brook (Annapolis County) on the northern tributary.

The river was a major transportation route for the Mi'kmaq people of Nova Scotia.

There are a number of hydroelectric projects on the river, which has been exploited for more than a hundred years.

Smallmouth bass has been found in the Mersey and neighbouring watersheds.