Upton was appointed on August 14, 1953, as a Republican to the U.S. Senate to fill the vacancy caused by the death of Charles W. Tobey, and served from August 14, 1953, to November 7, 1954; he was an unsuccessful candidate for nomination to fill the vacancy. He resumed the practice of law, was a member of the Mixed Board, Clemency and Parole in Bonn, Germany in 1956, and was special ambassador to Liberia that year. He retired from law practice in 1970 and in 1972 died in Concord; interment was in Blossom Hill Cemetery.