The stream is the Swanee River of Stephen Foster (Foster, Stephen)'s famed song "Old Folks at Home." The river was named Guasaca Esqui (“River of Reeds”) by early Native American inhabitants, and its present name is thought to be a corruption of San Juanee (“Little St. John”). In the 1780s the secluded bays and inlets of Suwannee Sound were rendezvous points for pirates.

The Suwannee receives the waters of numerous springs and the Withlacoochee, Alapaha, and Santa Fe rivers. From its conjunction with the Withlacoochee, its channel is dredged for 135 miles (217 km); the last 25 miles (40 km) are tidal. In the north it flows over shoals and boulders and between cedar-lined limestone banks. Farther south its banks teem with cypresses, oaks, and various species of gardenias, orchids, and ixias. Bass, perch, catfish, bream, and small game are plentiful in and along the Suwannee.