Large-scale extinction is one of the defining challenges of our time, as human processes fundamentally and irreversibly reshape global ecosystems. While the extinction of large animals with popular appeal garners widespread public and research interest, the importance of smaller, less "charismatic" species to ecosystem health is increasingly recognized. Benefitting from systematically collected fossil and archaeological archives, we examined snake and lizard extinctions in the Guadeloupe Islands of the Caribbean. Study of 43,000 bone remains across six islands revealed a massive extinction of 50 to 70% of Guadeloupe's snakes and lizards following European colonization. In contrast, earlier Indigenous populations coexisted with snakes and lizards for thousands of years without affecting their diversity. Study of archaeological remains provides insights into the causes of snake and lizard extinctions and shows that failure to consider fossil-derived data probably contributes to substantial underestimation of human impacts to global biodiversity.