The tidal river course proceeds southwest into the Tangier Sound, Chesapeake Bay.

[2] A 26-mile ecotourism water trail running along the River was set aside in July 2011 by Delaware state and federal officials, contiguous with a 37-mile water-trail extending through Maryland to the Chesapeake Bay.

Notable towns and communities situated along the river include Nanticoke, Bivalve, Vienna, and Sharptown in Maryland; and further north the city of Seaford, Delaware.

According to a study paid for by the town of Vienna, the English explorer John Smith travelled up the Nanticoke River and mapped it, and visited with Native Americans in their settlement, now believed to be Vienna.

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