The resilience of a given species to hunting is conditioned by the effect of potential threats upon the more sensitive periods in its life history, such as when animals are breeding. We investigated the environmental drivers of breeding seasonality in the lowland paca (Cuniculus paca), and the potential impact of hunting on the species. As part of a participative study with hunters in 2 Amazonian sites, we obtained reproductive organs of pacas as well as information on the hunters’ daily wild meat extraction. Using data on rainfall, river water level, and fruiting phenology from the 2 study sites, we applied generalized additive models for location, scale, and shape (GAMLSS) to examine the effect of climatic and environmental factors on paca reproduction. Forest fruiting was directly linked to higher pregnancy rates in pacas, and when lactation and weaning of offspring mostly occurred. Hunting was highly seasonal in all studied years and positively correlated with higher levels of river water. The coincidence between hunting patterns and paca reproductive cycles during the wet season resulted in more pregnant females being harvested. In addition to the known slow reproductive rate of pacas, the disproportionate offtake of pregnant females may affect the long-term sustainability of hunting of this species. Reducing hunting during the flooded season may not be feasible because the lowland paca provides most of the wild meat consumed by thousands of rural Amazonians during this period. However, options to offset the negative effects of killing of pregnant females could include the zoning of hunting areas or encouraging hunters to target primarily males. Our results indicate that strategies for the sustainable harvest of pacas and other heavily hunted Amazonian mammals should consider the interaction between the species’ reproductive cycles and hunting by local people in order to enhance conservation and management efforts.