The river rises in Carroll County, Maryland, west of the unincorporated town of Harney at the Maryland-Pennsylvania border.

The 970 square mile watershed averages a flow of 600 million gallons per day (Mgal/d) at the mouth where it enters the Potomac River.

[3] The vegetation of the watershed is very similar to what one would expect to find through the Piedmont and valley and ridge regions, with some invasive species that threaten the balance of the ecosystem.

[4] However, it has one of the greatest nonpoint source pollution problems in the state due in large part to runoff from the 3,500 farms, livestock operations, and dairies in the watershed.

The Maryland Department of the Environment (MDE) has listed the Monocacy with impaired water quality for nutrient pollution, sediment, and fecal coliform bacteria.