Flaviviruses possess a conserved protease that is vital for viral maturation. We have designed catalytic metallopeptides for inactivation of both Zika and West Nile viral proteases, and potentially other viral homologues, by irreversible target destruction and low off-target activity against host proteases. Oxidative damage promoted by metallopeptides was characterized by mass spectrometry, localized to specific active site residues, and correlated with catalyst activity.