'apoenzyme' originates from Greek elements: the prefix 'apo-' (Greek 'ἀπό', apó) meaning 'away from' or 'separate', combined with 'enzyme' (from New Latin/Greek 'enzymon', from Greek 'ἔνζυμον' enzyma) meaning 'leavened' or 'in yeast' in original usage.

'enzyme' entered scientific English in the 19th century from New Latin/Greek 'enzymon'; 'apoenzyme' was formed by combining the Greek-derived prefix 'apo-' with 'enzyme' in late 19th to early 20th-century biochemical terminology to denote the enzyme protein separated from its cofactor. The modern term 'apoenzyme' has been used in biochemistry literature since that period.

Initially formed to denote the enzyme protein separated from its cofactor (literally 'away from enzyme's cofactor'), the meaning has remained specialized: the protein part of an enzyme lacking its cofactor, inactive until the cofactor binds (opposite of 'holoenzyme').