Entering the navy as a midshipman in 1800, Macdonough saw service during the U.S. war with Tripoli (1801–05). When war broke out with England, his major assignment was to cruise the lakes between Canada and the United States. When enemy ground forces threatened Plattsburg, N.Y.—the U.S. Army headquarters on the northern frontier—Macdonough's foresight and painstaking preparation for battle paid off. On Sept. 11, 1814, his 14-ship fleet met the British in the harbour and after several hours of severe fighting forced the 16-vessel squadron to surrender, thus saving New York and Vermont from invasion.

The victory brought Macdonough the thanks of the U.S. Congress and promotion to captain. More important, it left the British no grounds for territorial claims in the Great Lakes area at the peace negotiations that followed. In failing health, he died en route home after serving on various European assignments.