'small-molecule' originates from English, combining the adjective 'small' (Old English 'smæl' meaning 'small, thin') and the noun 'molecule' (from Latin 'molecula', diminutive of 'moles' meaning 'mass' or 'barrier').

'molecule' came into English via Latin 'molecula' and French 'molécule'; the compound form 'small molecule' is a modern English formation (20th century onward) used especially in chemistry and pharmacology; the hyphenated form 'small-molecule' is a stylistic/compound adjective form.

Originally 'molecule' denoted a 'little mass' in Latin; over time it came to mean the smallest particle of a chemical compound retaining its properties. 'Small-molecule' later evolved to specifically denote low–molecular-weight compounds, particularly in the context of drugs, as opposed to large biologics.