James Fenimore Cooper’s novel The Pathfinder, or The Inland Sea is set in the Oswego River valley.

[8] James Fenimore Cooper described the Oswego in these words: The Oswego is formed by the junction of the Oneida and the Onondaga,[note 1] both of which flow from lakes; and it pursues its way, through a gently undulating country, some eight or ten miles, until it reaches the margin of a sort of natural terrace, down which it tumbles some ten or fifteen feet, to another level, across which it glides with the silent, stealthy progress of deep water, until it throws its tribute into the broad receptacle of the Ontario.

The river drains an area of 5,122 square miles (13,266 km2), as large as the states of Rhode Island and Delaware together, comprising most of the Finger Lakes region of upstate New York.

The Oswego River was listed as a Great Lakes Areas of Concern in The Great Lakes Water Quality Agreement between the United States and Canada until it was formally removed on July 21, 2006.

The river is stocked annually by the New York State Department of Environmental Conservation with 140,000 Chinook salmon and 20,000 steelhead.