'small-molecule-based' is a modern English compound formed from 'small molecule' + the adjective-forming element '-based'. 'small' originates from Old English 'smæl' where 'smæl' meant 'thin, little'; 'molecule' originates from Latin 'molecula' (a diminutive of 'moles') where 'moles' meant 'mass' and the diminutive suffix '-cula' indicated 'small'; 'base' (in '-based') ultimately comes via Old French from Latin/Greek 'basis' meaning 'foundation'.

'small-molecule-based' arose in late 20th-century scientific and pharmaceutical usage by compounding the phrase 'small molecule(s) based' into a hyphenated adjective; earlier usage would have described things as 'based on small molecules' or 'small-molecule drugs' before hyphenation became common.

The individual words originally referred simply to 'small' (little), 'molecule' (a tiny mass/particle), and 'base' (foundation); the compound came to mean specifically 'having its mechanism, design, or origin in small molecules' and is used mainly in scientific/medical contexts.