For the past 5 to 15 million years, marine iguanas (Amblyrhynchus cristatus), endemic to the Galápagos archipelago, experienced relaxed predation pressure and consequently show negligible anti-predator behavior. However, over the past few decades introduced feral cats and dogs started to prey on iguanas on some of the islands. We investigated experimentally whether behavioral and endocrine anti-predator responses changed in response to predator introduction. We hypothesized that flight initiation distances (FID) and corticosterone (CORT) concentrations should increase in affected populations to cope with the novel predators. Populations of marine iguanas reacted differentially to simulated predator approach depending on whether or not they were previously naturally exposed to introduced predators. FIDs were larger at sites with predation than at sites without predation. Furthermore, the occurrence of new predators was associated with increased stress-induced CORT levels in marine iguanas. In addition, age was a strong predictor of variation in FID and CORT levels. Juveniles, which are generally more threatened by predators compared to adults, showed larger FIDs and higher CORT baseline levels as well as higher stress-induced levels than adults. The results demonstrate that this naive island species shows behavioral and physiological plasticity associated with actual predation pressure, a trait that is presumably adaptive. However, the adjustments in FID are not sufficient to cope with the novel predators. We suggest that low behavioral plasticity in the face of introduced predators may drive many island species to extinction.