Caleb Blood Smith was born in 1808 in Boston, Massachusetts. He attended Cincinnati College and Miami University, studied law, and began to practice in Indiana. By 1831, Smith was involved in politics, copublishing a Whig newspaper, and, from 1833 to 1841, serving three terms in the Indiana state house of representatives.

Smith helped Whig candidate William Henry Harrison win the 1840 presidential election, though he failed in his own bid for the U.S. House of Representatives. He was more successful in 1842, and he served in the House from 1843 until 1849. Smith then served on the Board of Commissioners that addressed issues arising from the Mexican-American War of 1850. He also worked as president of the Cincinnati and Chicago Railroad (1854-1859).In 1860, Smith became head of the Indiana state delegation to the Republican National Convention and supported Abraham Lincoln’s nomination for President. The following year, President Lincoln tapped Smith as his secretary of the interior, a position Smith held until 1862, when he resigned to become a justice on the Indiana Supreme Court. Caleb Blood Smith served in that capacity until his death in 1864.