After shakedown, Macdonough spent seven months as a training ship for midshipmen at the Naval Academy, Annapolis. 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 3d 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. During the summer of 1910, Macdonough took part in summer exercises 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.
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. Following this duty, on 27 March 1917, she commenced a recruiting cruise along the Mississippi River.
Following the United States entry into World War I in April, Macdonough took departure from New Orleans in mid-June 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, Macdonough 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 24 June and remained there until decommissioned on 3 September. Her name was struck from the Naval Register on 7 November 1919 and her hulk was sold for scrapping on 10 March 1920.