Aim. At least seven North American tribes specifically mention use of Eryngium (typically roots) as an anti-snake venom therapy. As snake envenomation is an endemic, life threatening medical risk, is there a scientific basis for the Native American ethnomedicine? Could this be demonstrated in an assay amenable to mechanistic evaluation and high throughput screening for later isolation and possible evaluation as a source for a lead drug? Methods. Proteases, mainly collagenases, are thought to be the main pathological agents in most American snake venoms. Water extracts of four plant parts of Eryngium yuccifolium were tested for enzyme inhibition in three highly sensitive in vitro protease assays, with multiple venoms. Results. Interestingly, activity was found in all plant parts, not just the roots, in the general protease assay, also in the more specific assay for collagenases, but less so for elastases where enzymatic activity was low, and against five species of American snake venoms. Inhibition spared the activity of a mammalian elastase, suggesting it has some specificity. In dose response assays, inhibitory activity in extracts of Eyngium a were noticeably more effective than randomly chosen plants, and comparable to some others. Conclusions. All data shown here are consistent with pharmacological inhibition of proteases in at least selected venoms of common venomous snakes by Eryngium extracts. And as the genus is widely distributed in America, the ethnological practice of using this plant as an anti-snake venom treatment is supportable, may have been common, and suggests further bioactivity and phytochemical studies are warranted. [J Complement Med Res 2016; 5(3.000): 219-225]