Archaeologists have long envisioned direct encounters between Paleoindians and megafauna of the Last Glacial-Interglacial Transition (LGIT, 15–11.5 cal BP). Debate continues regarding the role that these Paleoindian hunters played in the extinction event(s). Archaeologists, paleontologists, and paleobiologists have proposed that Paleoindians proved to be very effective hunters who employed darts and spears tipped with razor-sharp, chipped-stone projectile points. These weapons are assumed to have been capable of inflicting mortal wounds and death as a result of massive blood loss. Few archaeologists, however, have considered the possible use of hunting poisons, as well as the implications of poison use for past procurement tactics and present-day archaeological research. This paper explores the feasibility of poison hunting by Paleoindians—specifically those derived from Aconitum spp. or monkshood—as well as the possible material correlates of this technology that might be observed in the archaeological record.