Jaguars (Panthera onca) exert critical top-down control over large vertebrates across the Neotropics. Yet, this iconic species have been declining due to multiple threats, such as habitat loss and hunting, which are rapidly increasing across the New World tropics. Based on geospatial layers, we extracted socio-environmental variables for 447 protected areas across the Brazilian Amazon to identify those that merit short-term high-priority efforts to maximize jaguar persistence. Data were analyzed using descriptive statistics and comparisons of measures of central tendency. Our results reveal that areas containing the largest jaguar densities and the largest estimated population sizes are precisely among those confronting most anthropogenic threats. Jaguars are threatened in the world’s largest tropical forest biome by deforestation associated with anthropogenic fires, and the subsequent establishment of pastures. By contrasting the highest threats with the highest jaguar population sizes in a bivariate plot, we provide a shortlist of the top-10 protected areas that should be prioritized for immediate jaguar conservation efforts and 74 for short-term action. Many of these are located at the deforestation frontier or in important boundaries with neighboring countries (e.g., Peruvian, Colombian and Venezuelan Amazon). The predicament of a safe future for jaguars can only be ensured if protected areas persist and resist downgrading and downsizing due to both external anthropogenic threats and geopolitical pressures (e.g., infrastructure development and frail law enforcement).