Having lost reelection to the House in 1864, Creswell was elected to the U.S. Senate to fill the vacancy caused by the death of Thomas H. Hicks, serving from 1865 until the end of that term in 1867. During his time in the Senate, he served as chairman of the Committee on the Library in the 39th Congress. At the Republican National Convention in 1868, Creswell's name was put forward for either the presidential or vice presidential nominations.