His paternal grandfather, Charles Lowndes, had moved his family from St. Kitts in the British West Indies in 1730 to South Carolina, but his extravagant spending led to financial ruin.

After he committed suicide, his sons Charles and Rawlins were placed in the care of Robert Hall, then the provost-marshal of South Carolina (its chief law enforcement officer).

He acquired his first plantation along the Stono River in St. Paul Parish in 1748 (which qualified him for a seat in the lower house of the South Carolina Assembly), although that wife died in childbirth in 1750.

Elected to the Twelfth United States Congress as a Representative from the Charleston area, Lowndes was a key member of the 'War Hawk' faction along with Speaker of the House Henry Clay, future President of the Second Bank of the United States Langdon Cheves, Tennessee representative Felix Grundy, and future Vice President and South Carolina Senator John C. Calhoun.

His reputation for financial expertise made Lowndes a chief lieutenant of Calhoun in authorizing the Second Bank of the United States during the Fourteenth Congress.

According to historians Jeanne and David Heidler, "Admired for his fairness and judicious temperament, Lowndes was frequently mentioned as presidential timber, especially because he seemed immune to ambition.

At his wife's urging, the Lowndes family embarked for a recuperative visit to England, but William died en route on October 27, 1822, at the age of 40.