An important challenge for conservation is a quantitative understanding of how multiple human stressors will interact to mitigate or exacerbate global environmental change at a community or ecosystem level. We explored the interaction effects of fishing, ocean warming, and ocean acidification over time on 60 functional groups of species in the southeastern Australian marine ecosystem. We tracked changes in relative biomass within a coupled dynamic whole-ecosystem modeling framework that included the biophysical system, human effects, socioeconomics, and management evaluation. We estimated the individual, additive, and interactive effects on the ecosystem and for five community groups (top predators, fishes, benthic invertebrates, plankton, and primary producers). We calculated the size and direction of interaction effects with an additive null model and interpreted results as synergistic (amplified stress), additive (no additional stress), or antagonistic (reduced stress). Individually, only ocean acidification had a negative effect on total biomass. Fishing and ocean warming and ocean warming with ocean acidification had an additive effect on biomass. Adding fishing to ocean warming and ocean acidification significantly changed the direction and magnitude of the interaction effect to a synergistic response on biomass. The interaction effect depended on the response level examined (ecosystem vs. community). For communities, the size, direction, and type of interaction effect varied depending on the combination of stressors. Top predator and fish biomass had a synergistic response to the interaction of all three stressors, whereas biomass of benthic invertebrates responded antagonistically. With our approach, we were able to identify the regional effects of fishing on the size and direction of the interacting effects of ocean warming and ocean acidification.