In 1815 Macdonough took command of the Portsmouth naval yard. In 1818 he took command of the USS Guerrier 44 gun frigate. He got tuberculosis, but remained on duty. He commanded the USS Ohio that has 74 guns and was being built in New York Harbor. He went to Niagara Falls and sailed down the ST Lawrence in a small boat all the way to Quebec. Next he took command of the USS Constitution in 1824. His wife died from Tuberculosis and a couple months later Macdonough died at sea from Tuberculosis. They were both buried in Middletown, Connecticut.