'nonpeptidyl' is formed from the negative prefix 'non-' (from Old English 'nān' meaning 'not') plus 'peptidyl' (derived from 'peptide' with the chemical suffix '-yl' indicating a radical or derivative).

'peptide' comes from Greek(pept- / peptos 'digested') via Neo-Latin and modern chemical nomenclature; the suffix '-yl' was adopted in chemical terminology in the 19th century to denote radicals/derivatives, producing 'peptidyl'; in 20th-century scientific usage the prefix 'non-' was attached to form 'nonpeptidyl' to describe compounds that are not peptide-based.

Originally the Greek root related to 'digested' (pept-), later 'peptide' came to mean a chain of amino acids; with the suffix '-yl' it signified a peptide-derived group, and 'nonpeptidyl' evolved to mean 'not peptide-derived' or 'not peptide in nature.'