Abstract Anthropogenic environmental change is predicted to disrupt multitrophic interactions, which may have drastic consequences for population-level processes. Here, we investigate how a large-scale human-mediated disturbance affects the abundance of North America’s most venomous caterpillar species, Megalopyge opercularis. Specifically, we used a natural experiment where netting was deployed to cover the entire canopies of a subset of mature southern live oak trees (Quercus virginiana) to exclude urban pest birds (grackles and pigeons), throughout an 8.1-km2 area encompassing a medical center in Houston, Texas. We used this experimental exclusion to test the following hypothesis: release from avian predators increases caterpillar abundance to outbreak levels, which increases the risk to human health. Results from a multi-year survey show that caterpillar abundance increased, on average, >7300% on netted versus non-netted trees. Thus, increases in caterpillar abundance, due to anthropogenic enemy release, increase human exposure to this venomous pest, and should be considered a health threat in the area. This study emphasizes the unforeseen consequences of ecological disturbance for species interactions and highlights the importance of considering ecology in urban planning.