'coenzyme' originates from the English combining form 'co-' (from Latin 'com') and 'enzyme' (from German 'Enzym', ultimately from Greek 'enzymon'), where 'co-' meant 'together' and 'enzymon' meant 'in leaven'.

'coenzyme' initially appeared as the hyphenated form 'co-enzyme' in early 20th-century biochemical literature and later solidified into the single word 'coenzyme'. The element 'enzyme' itself entered English from German 'Enzym', which came from Greek 'enzymon' (en- 'in' + zyme 'leaven').

Initially used to denote a substance that acts together with an enzyme, the term has retained this core sense but has become more specifically applied to small organic molecules (often vitamin-derived) that transiently participate in enzyme-catalyzed reactions.