In 1869, he moved to Omaha, Nebraska, and continued to practice law, and was the city attorney of Omaha for six years, as well as being a member of the State constitutional conventions in 1871 and in 1875. Manderson was elected as a Republican to the U.S. Senate in 1883, was reelected in 1888 and served from March 4, 1883, to March 3, 1895. During the Fifty-first, Fifty-second and Fifty-third Congresses, Manderson served as president pro tempore of the United States Senate. He was also chairman of the Committee on Printing in the Forty-eighth through Fifty-second Congresses.
Manderson was appointed general solicitor of the Burlington system of railroads west of the Missouri River, and was vice president of the American Bar Association in 1899 and president in 1900. He died on board the steamship Cedric in the harbor of Liverpool, England, on September 28, 1911, and was interred in Forest Lawn Cemetery, Omaha.
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