'macromolecular' originates from a combination of Greek and New Latin: Greek 'makros' (meaning 'large') combined with New Latin/Modern Latin 'molecularis' (from Latin 'molecula', a diminutive of 'moles' meaning 'mass').

'macromolecular' developed in modern scientific English (primarily in the 19th–20th centuries) by combining the prefix 'macro-' with the adjective 'molecular'. The noun 'molecule' entered scientific use from Latin 'molecula' in the 17th century, and the combined form became common in chemistry and biochemistry in the 20th century.

Initially a literal combination meaning 'large' + 'molecular' (i.e., pertaining to large molecules); over time it came to be used specifically for properties, structures, and phenomena of macromolecules such as polymers, proteins, and nucleic acids.