Goff was appointed by President Woodrow Wilson as general counsel of the United States Shipping Board in 1920 and later became a member, serving until 1921; he was appointed an assistant to the Attorney General on several occasions from 1920 to 1923. He returned to Clarksburg in 1923 and was elected as a Republican to the U.S. Senate and served from March 4, 1925, to March 3, 1931; he was not a candidate for renomination in 1930.
While in the Senate, he was chairman of the Committee on Expenditures in Executive Departments (Seventy-first Congress). He resided in Washington, D.C. and died at his winter home in Thomasville, Georgia, in 1933, aged 66. Interment was in Arlington National Cemetery.
Guy D. Goff was a son of Nathan Goff, a U.S. Senator and Representative from West Virginia, and was the father of Louise Goff Reece, a U.S. Representative from Tennessee.