Talbot served in the Kentucky Senate from 1812 to 1815. He was then elected as a Democratic Republican to the United States Senate to fill the vacancy caused by the resignation of Senator Jesse Bledsoe, and served from February 2, 1815, to March 3, 1819. The second time he was elected to the United States Senate was to fill the vacancy caused by the resignation of William Logan, and served from October 19, 1820, to March 3, 1825. He then resumed his law practice and died on his plantation near Frankfort.
Isham Talbot was interred in the State Cemetery in Frankfort.