After graduation he studied for two years at the Columbia Law School. He received the degree of LL.B. in 1869, and was admitted to the bars of Rhode Island and New York the same year, although he never practiced. He had always taken an active interest in politics and in 1880 and 1884 was a presidential elector. He was elected Governor of Rhode Island in 1885 and served two terms, but was defeated for a third term. He was a member of the commission that built the new Rhode Island State House at Providence.

In 1894 he was elected as a Republican to the United States Senate, receiving the unanimous vote of the General Assembly in Senate, House, and joint convention. He was twice reelected to the Senate, his last term ending March 4, 1913. In the Senate, Wetmore was, first, chairman of the Committee on Manufactures, and then chairman of the Joint Committee on the Library for sixteen years. He was also a member of the Appropriations, District of Columbia, Naval Affairs, Public Buildings and Grounds, and other committees.

He had a deep interest in the building up of the Navy and the development of the naval base in Narragansett Bay. He served as chairman of the joint commission appointed by Congress to prepare plans for the completion of the Capitol building in Washington; was chairman of the first Lincoln Memorial Commission and a member of the commission that erected the National Lincoln Memorial in Washington; and was a member of the Grant Memorial Commission, as well as many others for the erection of statues and memorials. He was greatly interested in the improvement and development of Washington and the District of Columbia on a definite artistic plan, and was particularly identified with the legislation creating the National Commission of Fine Arts.

In private life Mr. Wetmore was for many years associated with various organizations for promoting the fine arts. He was one of the organizers of the Metropolitan Opera in New York and a member of the committee in charge of the construction of the Metropolitan Opera House. He was a trustee of the Peabody Museum of Natural History at Yale and of the Peabody Education Fund. In 1888 he was nominated as a Fellow of the University, but declined to have his name considered. He was one of the founders of the Jockey Club, vice president of the National Horse Show Association of America, and a director of other organizations for improving the breeding of horses.

At his home in Newport he was a trustee of the Redwood Library and Athenaeum, president and a trustee of the Newport Hospital, and president of the Newport Reading Room and the Newport Casino. He was a member of the Society of the Cincinnati.

He was married December 22, 1869, in New York City, to Edith Malvina Keteltas. Her father, Eugene Keteltas, had been a member of the Yale College Class of 1822, but left before graduation, and was graduated at Union College in 1822. Yale gave him the honorary degree of M.A. in 1870. Mrs. Wetmore's grandfather, Philip Doddridge Keteltas, was Yale 1792; her great-grandfather, Rev. Abraham Keteltas, graduated at Yale in 1752 and was admitted to the M.A. degree at Yale and Princeton University in 1755; and her great-great-grandfather, William Smith, was Yale 1719.

Mr. and Mrs. Wetmore had four children: Edith Malvina Keteltas; Maude Alice Keteltas; William Shepard Keteltas (B.A. 1897); and Rogers Pickman Derby Keteltas.

Mr. Wetmore died September 11, 1921, in Boston.