Completing his legal education in 1806, Calhoun returned to South Carolina and passed the state bar the next year. He established a law practice but was soon elected to the state legislature in 1808. After one term, he won the first of three consecutive terms in the U.S. House (1811-1817) as a Jeffersonian-Republican. Calhoun was among a small but influential group of Congressional "War Hawks" agitating for war against Great Britain, which was finally declared in June 1812. A few months earlier, Calhoun assumed the chairmanship of the House Foreign Relations Committee, and was a leading nationalist by the end of the war. In 1816 he drafted the bill reestablishing a national bank and voted for a protective tariff.

In 1817 President James Monroe named Calhoun to be secretary of war. The War Department was in disarray after years of mismanagement, so Calhoun continued the reforms begun by the previous acting-secretary, William Crawford. Secretary Calhoun pushed for the westward migration of Cherokees from their homeland in Georgia, and he approved valuable surveying expeditions in the Northwest. When General Andrew Jackson exceeded his orders and seized Spanish Florida, Calhoun argued in a cabinet meeting for repudiating and disciplining him. Secretary of State John Quincy Adams, however, convinced President Monroe to back up the general. Adams then used Jackson's conquest to negotiate the purchase of Florida and other concessions from Spain.

In 1824 the Republican Congressional Caucus nominated Calhoun for president, but he dropped out of the race when other candidates-Jackson, Adams, Crawford, and Henry Clay-proved to be more popular. Instead, he sought the vice-presidency unopposed and was duly elected. When no presidential candidate secured an electoral-college majority, the contest was thrown into the House, which selected Adams over Jackson, even though the latter had received the most electoral and popular votes. Although Calhoun was Adams' vice president, the South Carolinian supported the disgruntled Jackson and his new Democratic party. He engaged anonymously in a series of newspaper debates over the proper role of a vice-president with an epistolary antagonist was rumored to be President Adams. The exchange highlighted Calhoun's command of political theory and forensics.

When Congress enacted a new tariff in 1828, many Southerners, especially in South Carolina, concluded that the "tariff of abominations" would be detrimental to the region's economy. Calhoun anonymously wrote a political tract, "The South Carolina Exposition and Protest," which argued that the federal Constitution was simply a contract between sovereign states; that each state had the right to nullify within its borders any federal law that violated its vital interest; and that any state had the right to secede if it determined that its rights and interests were being violated or ignored by the federal government.

Later in 1828 Calhoun was reelected vice president, this time serving under President Andrew Jackson. When Calhoun's authorship of the "Exposition" became known, it created a hostile relationship between him and the new president, who was upholding federal authority. Secretary of State Van Buren worked to widen the breech by reminding Jackson of Calhoun's previous attempt to reprimand him for taking Spanish Florida. Calhoun fell into further disfavor when his wife convinced other cabinet wives to shun Peggy Eaton, the wife of Secretary of War John Eaton, for allegedly having an affair with Eaton before her first husband died. The president took the situation very personally since it conjured up memories of allegations against his beloved late wife, Rachel. Van Buren convinced Jackson to reshuffle his cabinet, replacing Calhoun partisans with Van Buren favorites. When Congress reconvened in December 1831, it defeated Van Buren's appointment as minister to Great Britain by Calhoun's tie-breaking vote.

In the 1832 presidential campaign, Jackson replaced Calhoun as his running-mate with Van Buren. Calhoun resigned from the vice presidency and was elected by the South Carolina legislature to the U.S. Senate. Meanwhile, Congress revised the tariff but not to the satisfaction of South Carolinians, so a special state convention applied Calhoun's theory and nullified the tariff within South Carolina. The governor also called up the state militia to defend state interests. President Jackson threatened to use the military to enforce the tariff, while Calhoun worked with Henry Clay to draft a compromise tariff that lowered rates gradually over time. It passed Congress in early 1833 and the "Nullification Crisis" was defused.

Underlying the tariff issue was the slavery question. The antislavery movement was expanding in the United States and Western Europe, and the failed Nat Turner Rebellion of 1831 in Virginia raised concerns among slaveholders throughout the South. Thus it seemed imperative to Calhoun that the Southern economic system could not be tampered with by the federal government. During his tenure in the U.S. Senate (1832-1843; 1845-1850), Calhoun rigorously defended the institution of slavery and Southern interests attendant to it. In 1844-1845 he served as secretary of state under President John Tyler, completing final arrangements for the annexation of Texas, which he favored as an addition of more slave territory to the Union.