Combining earnings from both passenger and military rates, Guthrie ensured that the line's infrastructure at the close of the war was superior to what it had been before the war started. Guthrie was a delegate to the 1864 Democratic National Convention in Chicago. He voted for the ticket of General George B. McClellan and former Kentucky governor Thomas Bramlette for president and vice-president, respectively. At the convention, he also opposed the Wade–Davis Bill. The Kentucky Senate narrowly chose Guthrie over fellow Louisvillian and Union general Lovell H. Rousseau for a seat in the U.S. Senate in 1865. Senator Guthrie opposed the Republican Party's Reconstruction efforts. Guthrie supported President Andrew Johnson, opposed the Freedmen's Bureau and the passage of the Fourteenth Amendment. On February 7, 1868, Guthrie resigned his position due to ill health. He suffered a stroke on April 8, 1868, which left him paralyzed and bedridden for the rest of his life. On June 11, 1868, he resigned as president of the Louisville and Nashville Railroad, recommending General William Tecumseh Sherman to be his successor. Guthrie died in Louisville on March 13, 1869, and was buried in Cave Hill Cemetery. The city of Guthrie, Kentucky, and Guthrie Street in Downtown Louisville are named in his honor. The United States Revenue Cutter Service, a branch of the Treasury, named small patrol vessels after Guthrie, in 1868, 1888 and 1895.