Lowell entered the Union army in June 1861, and was commissioned as a captain in the 3rd (afterwards 6th) U.S. Cavalry. On April 15, 1863, he became Colonel of the 2nd Massachusetts Cavalry. He was fatally wounded in the Battle of Cedar Creek on October 19, 1864, when he was promoted brigadier general of U.S. Volunteers, and died on the next day at Middletown, Virginia, at the age of 29. Upon hearing of his death, Brig. Gen. George Armstrong Custer wept and Maj. Gen. Philip Sheridan remarked "I do not think there was a quality which I could have added to Lowell. He was the perfection of a man and a soldier."
In October 1863, Lowell married Josephine Shaw (1843 – 1905), a sister of Colonel Robert Gould Shaw, one of his close friends. Her home when she was married was on Staten Island, and she became deeply interested in the social problems of New York City. She was a member of the State Charities Aid Society, and from 1867 to 1889 was a member of the New York State Board of Charities, being the first woman appointed to that board. She founded the Charity Organization Society of New York City in 1882, and wrote Public Relief and Private Charity (1884) and Industrial Arbitration and Conciliation (1893).