It flows through the Red Hills, the Jackson Bluff Dam, Talquin State Forest, Lake Talquin State Park and the Apalachicola National Forest, and past Ochlockonee River State Park, where it is tidally influenced and a mixture of fresh, brackish, and salt water,[3] on the way to its terminus in Ochlockonee Bay, which then empties into Apalachee Bay, with tidal influences extending upstream over 15 miles (24 km) from the river's mouth.

[4] When the Spanish arrived in northern Florida, the Ochlockonee River formed the western boundary of their Apalachee Province.

On 29 December 1863, Stars and Stripes sank the blockade-running schooner Caroline Gertrude, aground on the sandbar at the mouth of the Ochlockonee.

On 19 and 20 October 1864, Stars and Stripes destroyed an extensive Confederate fishery at Mashes Island and captured the troops stationed there as guards.

[7] Rare animals that can be found along the Ochlockonee include red-cockaded woodpecker, least tern, and the Apalachicola dusky salamander.

[7] The river is especially rich in rare freshwater mussels (Unionidae), including three federally listed endangered species: the Ochlockonee moccasinshell, the Shinyrayed pocketbook, and the Oval pigtoe.

Fishing on the Ochlockonee Bay is excellent for Flounder, Redfish, Black Drum, Spotted Sea Trout, Blue Crab and sharks.