Some of the main tributaries that feed the Nanticoke on the west-side include: Cow Creek; Jack Creek; Wapremander Creek; Marshyhope Creek; and the east side: Gravelly Fork and Broad Creek. 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.
The river was dredged in 1990 to facilitating shipping travel along the course. As of 2012[update], a project to once again dredge the channel is on hold for financial reasons.