He was elected as a Democrat to the 33rd, and served from March 4, 1853, to March 3, 1855. In his first term in Congress, Fenton strongly opposed the Kansas-Nebraska Act of 1854 and unsuccessfully tried to persuade President Franklin Pierce and U.S. Secretary of State William L. Marcy to oppose the bill. He was defeated for reelection that year. He was again elected, now as a Republican, to the 35th, 36th, 37th and 38th United States Congresses, and served from 1857 to 1865.
He was Governor of New York from 1865 to 1868. In 1868 he was among the candidates to be Vice President but the nomination went eventually to Schuyler Colfax. Afterwards he was elected to the U.S. Senate and served from 1869 to 1875. In 1872 he was among the Republicans opposed to President Ulysses S. Grant who joined the short-lived Liberal Republican Party.
In 1878, he represented the United States at the international monetary conference in Paris.
Fenton was known as "The Soldiers' Friend" for his efforts to help returning Civil War veterans. Fenton worked to remove tuition charges for public education, helped to establish six schools for training teachers, and signed the charter for Cornell University.
After his death, a building at The State University of New York at Fredonia, Fenton Hall, was named in his honor because he had attended the previous incarnation of the school, the Fredonia Academy.
His former home in Jamestown is the site of the Fenton Historical Society.