The name "Musquodoboit" is Mi'kmaq, roughly translated to "beautiful water". It rises in the extreme northeastern part of the county near the boundary with Pictou and Guysborough counties. Rising in the Cobequid Mountains, the river runs in a southwesterly direction along the Halifax-Colchester county line through the fertile Musquodoboit Valley; Glenmore Mountain is on the north and a series of low hills are on the south.
Near the halfway point, the river changes course at a right angle, running toward the southeast where it empties into a bay on the Atlantic Ocean called Musquodoboit Harbour. other communities along its length include Middle Musquodoboit, Moose River, Elderbank, Meaghers Grant and Upper Musquodoboit. Dollar Lake flows into the Musquodoboit River.