Significance Marine reserves that prohibit fishing are a critical tool for sustaining coral reef ecosystems, yet it remains unclear how human impacts in surrounding areas affect the capacity of marine reserves to deliver key conservation benefits. Our global study found that only marine reserves in areas of low human impact consistently sustained top predators. Fish biomass inside marine reserves declined along a gradient of human impacts in surrounding areas; however, reserves located where human impacts are moderate had the greatest difference in fish biomass compared with openly fished areas. Reserves in low human-impact areas are required for sustaining ecological functions like high-order predation, but reserves in high-impact areas can provide substantial conservation gains in fish biomass.