'holoenzyme' originates from modern scientific English, formed by combining the Greek prefix 'holo-' meaning 'whole' and the noun 'enzyme' (from Greek 'enzymon', 'in leaven').

'holo-' (from Greek 'holos', "whole") was attached to the 19th–20th century coinage 'enzyme' (via German and modern scientific usage) to form 'holoenzyme' in 20th century biochemical literature, denoting the 'whole' enzyme complex (apoenzyme plus cofactors).

Initially and still, it meant 'the whole/complete enzyme (apoenzyme plus its cofactors)'; the technical sense has remained consistent as biochemical knowledge refined the roles of cofactors.