Millions of people rely on the ecosystem services provided by coral reefs, but sustaining these benefits requires an understanding of how reefs and their biotic communities are affected by local human-induced disturbances and global climate change. Ecosystem-based management that explicitly considers the indirect and cumulative effects of multiple disturbances has been recommended and adopted in policies in many places around the globe. Ecosystem models give insight into complex reef dynamics and their responses to multiple disturbances and are useful tools to support planning and implementation of ecosystem-based management. We adapted the Atlantis Ecosystem Model to incorporate key dynamics for a coral reef ecosystem around Guam in the tropical western Pacific. We used this model to quantify the effects of predicted climate and ocean changes and current levels of current land-based sources of pollution (LBSP) and fishing. We used the following six ecosystem metrics as indicators of ecosystem state, resilience and harvest potential: 1) ratio of calcifying to non-calcifying benthic groups, 2) trophic level of the community, 3) biomass of apex predators, 4) biomass of herbivorous fishes, 5) total biomass of living groups and 6) the end-to-start ratio of exploited fish groups. Simulation tests of the effects of each of the three drivers separately suggest that by mid-century climate change will have the largest overall effect on this suite of ecosystem metrics due to substantial negative effects on coral cover. The effects of fishing were also important, negatively influencing five out of the six metrics. Moreover, LBSP exacerbates this effect for all metrics but not quite as badly as would be expected under additive assumptions, although the magnitude of the effects of LBSP are sensitive to uncertainty associated with primary productivity. Over longer time spans (i.e., 65 year simulations), climate change impacts have a slight positive interaction with other drivers, generally meaning that declines in ecosystem metrics are not as steep as the sum of individual effects of the drivers. These analyses offer one way to quantify impacts and interactions of particular stressors in an ecosystem context and so provide guidance to managers. For example, the model showed that improving water quality, rather than prohibiting fishing, extended the timescales over which corals can maintain high abundance by at least 5–8 years. This result, in turn, provides more scope for corals to adapt or for resilient species to become established and for local and global management efforts to reduce or reverse stressors.