How reliable is our knowledge of even the most prominent functional traits in extensively studied venomous animals? This study adopts rattlesnakes as a model group to investigate the evolutionary history of venom coagulotoxicity and its most relevant medical implications. Venom-induced clotting of human plasma and fibrinogen was determined and mapped onto the phylogenetic tree of rattlesnakes to reconstruct the evolution and diversity of coagulotoxic activity across the group. Our results indicate that venom phenotype is often independent of phylogenetic relationships, rather suggesting a relevant influence of diet and other environmental factors on venom evolution. We report the first instance of true procoagulant venom activity in Neotropical rattlesnakes for the species Crotalus culminatus, whose ontogenetic clotting factor-activating pattern emphasized the need for more accurate research on the mechanisms of rattlesnake envenomation. Underscoring this unmet need, one of the mainstream Mexican antivenoms (Antivipmyn®) failed to neutralize the coagulotoxic action of C. culminatus venom, highlighting potential issues in snakebite management for this species. On the other hand, metalloprotease inhibitors were able to effectively counter the procoagulant activity of the venom, not only indicating that this enzyme class is likely responsible for the pathophysiological actions, but also that metalloproatease inhibitors may have therapeutic benefit in treating the envenomed patient. Ultimately, our findings highlight that activity rather than protein composition is the target of selection pressure in venom evolution and underscore the need for further research into rattlesnake venom patterns from a functional perspective. Such remarkable, yet long overlooked variability in venom activity also bears considerable clinical relevance in terms of the impact of rattlesnake envenoming and potential shortfalls of current antivenom treatments.