'antifederalism' originates from English, specifically formed from the prefix 'anti-' (from Greek 'anti') and the noun 'federalism' (ultimately from Latin 'foedus' via Medieval Latin and French), where 'anti-' meant 'against' and Latin 'foedus' meant 'covenant' or 'treaty'.

'federal' traces back to Latin 'foedus' (a covenant), passed into Medieval Latin as 'foedalis' and into French as 'fédéral', then entered English as 'federal'; 'federalism' (the -ism noun) developed later, and 'antifederalism' was coined in English to denote opposition to federal arrangements, notably in the late 18th century U.S. context.

Initially it referred specifically to organized opposition to the establishment or strengthening of a federal system (notably the 18th-century Antifederalists); over time it has maintained that core meaning while also being used more broadly for any opposition to federal forms of government or centralization.