Polyphenolic natural products from green tea and red wine have been identified as metalloproteinase inhibitors. Members from the flavonoid and stilbene families found to possess metalloproteinase inhibitory activities include (−)-epigallocatechin gallate, (−)-epicatechin gallate and piceatannol, but their minimally active pharmacophores have not been evaluated. The present study has examined compounds that are structural components of or structurally related to (−)-epigallocatechin gallate, (−)-epicatechin gallate and piceatannol for inhibition of aggrecanases and four representative matrix metalloproteinases. Piceatannol and pyrogallol were found to inhibit all aggrecanases and matrix metalloproteinases studied, indicating a crucial reliance on multiple hydroxyl groups for (−)-epigallocatechin gallate, (−)-epicatechin gallate and piceatannol activity. Differences in Ki values for pyrogallol as determined with two structurally distinct substrates indicated the likelihood that this compound binds in a non-competitive modality. Further analysis showed that pyrogallol acts as an exosite inhibitor, consistent with the action of (−)-epigallocatechin gallate. In contrast, piceatannol was shown to be a competitive binding inhibitor and showed no differences in apparent Ki values as determined by distinct substrates, illustrating the benefits of using two structurally distinct substrates to assist the analysis of protease inhibitors. The compounds identified here could be utilized to develop novel metalloproteinase probes or as fragment components of more active inhibitors.