Crown-of-thorns starfish (CoTS) outbreaks rank among the greatest threats to coral throughout the Indo-Pacific. In the future, reefs already stressed by CoTS will be further burdened by overfishing and nutrient loading. How much these two factors will exacerbate CoTS outbreak severity is still uncertain. Furthermore, the CoTS management literature has focused on the Great Barrier Reef, whereas outbreak damage is rising across the Indo-Pacific. Here, we use a metacommunity model to simulate CoTS outbreaks in areas with high and growing levels of fishing pressure and offshore nutrient input. We model outbreaks on reefs adjacent to two cities within the range of CoTS that have less prior literature coverage: Cebu City, Philippines, and Jeddah, Saudi Arabia. We observe that the combination of population increases and urbanization of previously rural areas can drive complex patterns of multi-stressor interaction. We find that CoTS removal on intermediate spatial scales significantly improves regional-scale coral health, and provide guidelines under which each of four CoTS management strategies is optimal for conservation. We find that coral decline due to overfishing can be sharper on reefs with CoTS, and that nutrification can induce a shift from discrete outbreak waves to continuous CoTS presence. Our work shows the importance of long-term planning for reef management, and highlights how reef stressors can interact in potentially unforeseen ways.