He was admitted to the bar, and began his legal practice in Versailles, Kentucky. He moved to Frankfort, Kentucky, where he also was a lawyer 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.
He was elected to the United States Senate a second time 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.
Member Kentucky; member United States Senate from Kentucky.