Macdonough failed to make the design speed of during trials, and along with her fellow Fore River-built destroyer Lawrence proved to have poor sea keeping. Both ships had their two 3-inch guns replaced by six-pounder guns, giving a gun armament of seven six-pounders. After shakedown, Macdonough spent seven months as a training ship for midshipmen at the United States Naval Academy, Annapolis, Maryland. On 31 May 1904, she joined the Coast Squadron, North Atlantic Fleet and for the next three years operated along the east coast and in the Caribbean. She was ordered to the Reserve Torpedo Fleet at Norfolk on 16 May 1907 and served with that fleet until the following year. Placed in full commission on 21 November 1908, Macdonough became the flagship of the 3rd Torpedo Flotilla and sailed for Pensacola, Florida. She participated in operations out of that port until the following spring when she returned to the east coast. During the summer of 1909, she cruised with the Atlantic Torpedo Squadron off New England. She then returned to the Gulf of Mexico and steamed up the Mississippi River for the St. Louis Centennial Celebration. Returning to the east coast in December, she was placed in reserve at Charleston, South Carolina on the 16th. Macdonough took part in summer exercises during the summer of 1910 and returned to Charleston, where, with the exception of two cruises to New York, she remained for the next two years. In 1913 and 1914, she conducted summer cruises for the Massachusetts Naval Militia.
World War I
On 29 January 1915, Macdonough was detached from the Reserve Torpedo Flotilla and assigned to the Submarine Flotilla, Atlantic Fleet. For the next two years, she operated with submarines in maneuvers and exercises from Pensacola to Newport, Rhode Island. Following this duty, she commenced, on 27 March 1917, a recruiting cruise along the Mississippi River. In mid-June the ship departed New Orleans, Louisiana for Charleston where she joined the Destroyer Force, Atlantic Fleet. Until January 1918, she performed screening assignments off the east coast. On 16 January 1918, she departed Philadelphia for Brest, France, arriving 20 February. She remained off the coast of France, providing escort and patrol services until 20 May 1919. Sailing for the United States, she arrived at Philadelphia on 24 June and remained in that port until decommissioned on 3 September. Her name was struck from the Naval Vessel Register on 7 November 1919 and her hulk was sold for scrapping on 10 March 1920.