Hale was an unsuccessful candidate for President of the United States on the Free Soil ticket in 1852. (See U.S. presidential election, 1852.)
He was again elected to the Senate in 1855 to fill the vacancy caused by the death of Charles G. Atherton. He was re-elected in 1859, in total serving from July 30, 1855, to March 3, 1865. He served as the chair of the Senate Republican Conference until 1862.