The river originates in Sabbathday Lake in New Gloucester and flows northeasterly into Auburn and then southerly through New Gloucester (via the Royal River Reservoir), Gray and North Yarmouth into Casco Bay at Yarmouth.

The river is bridged by Interstate 95 and U.S. Route 202 before leaving New Gloucester, then by the Maine Central Railroad "Back Road" and the Grand Trunk Railway in Auburn, and then again by the Grand Trunk Railway and by State Route 231 when it returns to New Gloucester.

One such mill was erected in 1872 by the Forest Paper Company on the current site of the Royal River Park.

The river is mentioned in several of Maine-native Stephen King's novels, including The Body, when the boys cross the Royal River, only to be attacked by leeches, as well as 'Salem's Lot and Rita Hayworth and Shawshank Redemption.

The McKin Company Superfund site was within the Royal River watershed.