Christopher Gadsden built one of Charleston's leading mercantile businesses, investing in ships, stores, plantations and a major wharf. His wealth depended partly on enslaved labour. Entering the Commons House of Assembly in the 1750s, he became a forceful opponent of imperial taxation and a leader of South Carolina's radical resistance. His advocacy of colonial liberty coexisted with his interests as a enslaver.

At the Stamp Act Congress in 1765, Gadsden urged cooperation across colonial boundaries rather than separate appeals based only on local privileges. He organised the Sons of Liberty and served in the Continental Congress in 1774–76. On its naval committee he supported the emerging Continental Navy. The yellow rattlesnake flag associated with him, carrying the warning Don't Tread on Me, became an emblem of resistance, although the wider use of snake symbolism predated his design.

Returning to South Carolina in 1776, he promoted independence, helped frame the state constitution and commanded the First South Carolina Regiment. He became a Continental brigadier general. A dispute with Robert Howe over military authority prompted his resignation in 1777 and later a duel in which neither was injured. In state politics he favoured disestablishment of the church and broader electoral participation, positions that brought him into conflict with conservative leaders.

As lieutenant governor during the British capture of Charleston in 1780, Gadsden became a prisoner. Taken to St Augustine, he refused a new parole under conditions he considered inconsistent with the surrender agreement and endured close confinement. After release, he declined election as governor in 1782, citing health and age, but continued public service and supported ratification of the United States Constitution in 1788. His career linked commercial power, revolutionary mobilisation and state-building, while exposing the exclusions within the liberty claimed by South Carolina's patriot leadership.