The river flows from the Appalachian Mountains to the Atlantic Ocean, for a total distance of about 301 miles (484 km).

The Savannah River's drainage basin extends into the southeastern Appalachian Mountains and the state of North Carolina, and is bounded by the Eastern Continental Divide.

[2] The Westo were thought to have migrated from the northeast, pushed out by the more powerful tribes of the Iroquois Confederacy, who had acquired firearms through trade.

During the American Civil War, President Abraham Lincoln proclaimed a blockade around the Confederate States of America, forcing merchantmen to use specific ports along the coast best suited for this purpose.

The harbor at Savannah became one of the busiest ports for blockade runners bringing in supplies for the Confederacy until it was cut off by the reduction of Fort Pulaski and Union capture of Cockspur Island.

[11] The South Carolina-Georgia border was originally defined in the Treaty of Beaufort in 1787, which, among other things, "[reserved] all islands in [the river] to Georgia".

[12] Between 1946 and 1985, the U.S. Army Corps of Engineers built three major dams on the Savannah for hydroelectricity, flood control, and navigation.

The site produced plutonium, tritium, and heavy water for the United States Atomic Energy Commission's nuclear weapons program.

The facility, now called the Savannah River Site and operated by the U.S. Department of Energy, still plays an important role in the economy of the Augusta metropolitan area.

In 1956 Clyde L. Cowan and Frederick Reines first detected neutrinos with an experiment carried out at the Savannah River Plant P-Reactor.

It is considered an alluvial river, draining a 10,577-square-mile (27,390 km2) drainage basin and carrying large amounts of sediment to the ocean.

River dredging operations to maintain the Port of Savannah have caused the estuary zone to move further upstream than its historical home.

Tributaries include: The Savannah River Basin in the Southeast region of the U.S. has been experiencing environmental change from anthropocentric activities.

[20] Through the building of several locks and dams in the first half of the 20th century (such as the New Savannah Bluff Lock and Dam, completed in 1937 during the Great Depression), and upstream reservoirs like Lake Hartwell, the Savannah River was once navigable by freight barges between Augusta, Georgia (on the Fall Line) and the Atlantic Ocean.

[21] When a large piece of equipment (a deaerator) needed to be delivered to the Vogtle Electric Generating Plant construction site in 2013, the barge travelled upstream from the Port of Savannah only to the Georgia Power's Plant McIntosh site, near Rincon, Georgia; from there, the cargo was moved by a road transporter.