John Bell was born in Mill Creek, Tennessee, to Margaret Edminston Bell and Samuel Bell, a blacksmith and a farmer. In 1814 he graduated from Cumberland College (Nashville) and two years later began to practice law. In 1817 he was elected to the state senate, then after serving one term he became a prominent attorney in Nashville. In 1827 he was elected to the U.S. House of Representatives, where he would serve seven consecutive terms. Although he personally opposed President Andrew Jackson's veto of the charter renewal for the Bank of the United States, Bell felt politically compelled to support the president's popular gesture. The congressman did, however, oppose efforts to remove bank deposits from the national bank. Bell was several times a losing candidate for speaker of the house, developing a rivalry with fellow Tennessean James K. Polk.

In the late-1830s Bell began affiliating with the nascent Whig party. In 1841 he was appointed by the first Whig president, William Henry Harrison, to be secretary of war, but served only a few months. Upon Harrison's sudden death, the new president, John Tyler, sided with the states' rights Democrats, provoking Bell and other cabinet members to resign in September 1841. For the next six years Bell invested in railroads and manufacturing, while working in Tennessee politics against Polk. Although his rival was elected president in 1844, Bell helped the Whig party deny the Democratic nominee victory in his home state.

In 1847 Bell was again elected to the state legislature, whose Whig majority promptly promoted him to the first of two terms in the U.S. Senate. He reluctantly supported the Compromise of 1850, which sought to quell the controversy over the expansion of slavery that the war with Mexico had reanimated. Although initially vacillating on the issue, Bell cast the only Southern vote in the Senate against the Kansas-Nebraska Act of 1854. Democrats took over the Tennessee legislature and denied Bell a third term, ending his Senate career in March 1859.

A remnant of the defunct Whig party reorganized as the Constitutional Union party and held a national convention in Baltimore in May 1860. Delegates nominated Bell for president and Edward Everett of Massachusetts for vice president. Their strategy was to win enough electoral votes to send the election into the House of Representatives, which, with four parties competing for the presidency, was a distinct possibility. In the final tally, though, Bell carried only three states-Tennessee, Kentucky, and Virginia-while Lincoln swept the north to win an electoral college majority.