'antifederal' originates from the prefix 'anti-' (from Greek 'anti' meaning 'against') combined with 'federal' (from Latin 'foedus' via French 'fédéral', meaning 'treaty, league' and by extension 'union/government structure').

'antifederal' developed as a compound (often written 'anti‑federal' or 'Anti‑Federal') in the late 18th century in English, especially in the United States during debates over the Constitution, and later became used more generally as 'antifederal'.

Initially it specifically described opponents of a particular federal constitution or the Federalists' policies (especially in the U.S. context); over time it broadened to mean any opposition to federalism or federal systems of government.