In 1864, during the American Civil War, one of the torpedo boats of Admiral David Dixon Porter's fleet ran into the Great Wicomico River and was captured.

The Great Wicomico flows into a trap-type estuary on Ingram Bay, with a history of significant natural spat settlement and seed oyster production.

[8] Large numbers of menhaden afflicted with lesions are periodically caught in the Great Wicomico, and a fish kill of at least 100,000 was observed by scientists in September, 2001.

Today, a lighthouse-shaped folly, not recognized as a navigational aid, marks the entrance of the river in Fleeton.

[8] State Route 200 crosses the river several kilometres from the mouth near the Athena Vineyards and Winery.