Lowndes entered South Carolina politics after a brief legal practice, serving in the state House of Representatives from 1804 to 1808. He supported public schooling and restrictions on further slave importation, while remaining part of a slaveholding plantation society. He helped devise the constitutional compromise of 1808, which adjusted legislative representation between the upcountry and the coastal districts. An unsuccessful state Senate candidacy preceded his election to Congress in 1810.

In the United States House from 1811, Lowndes joined the War Hawks who urged military preparations and war against Britain. He worked with Henry Clay and John C. Calhoun on defense and naval questions during the War of 1812. His committees covered Ways and Means and Foreign Affairs, placing him at the center of debates over revenue, tariffs, the national bank and relations with foreign powers. His influence rested on committee work and efforts to reconcile competing positions.

Lowndes participated in the struggle over Missouri's admission and the compromise arrangements intended to contain the dispute over slavery's expansion. He declined cabinet and diplomatic appointments while remaining in the House. Supporters in South Carolina proposed him for the presidency, but chronic ill health curtailed his prospects. He resigned his House seat in May 1822 and sailed for England in search of recovery. He died at sea that October, ending a national political career of just over a decade.