The oceans are increasingly affected by multiple aspects of global change, with substantialimpacts on ecosystem functioning and food-web dynamics. While the effects of single factors have beenextensively studied, it has become increasingly evident that there is a need to unravel the complexitiesrelated to a multiple stressor environment. In a mesocosm experimental study, we exposed a simplified,multi-trophic seagrass ecosystem (composed of seagrass, two shrimp species, and two intermediate predatoryfish species) to three global change factors consisting of simulated storm events (Storms), heat shocks(Heat), and ocean acidification (OA), and the combination of all three factors (All). The most striking resultindicated that when all factors were combined, there was a negative influence at all trophic levels, whilethe treatments with individual factors revealed species-specific response patterns. It appeared, however,that single factors may drive the multi-stressor response. All single factors (i.e., Storms, Heat, and OA) hadeither negative, neutral, or positive effects on fish and shrimp, whereas no effect was recorded for any singlestressor on seagrass plants. The findings demonstrate that when several global change factors appearsimultaneously, they can have deleterious impacts on seagrass ecosystems, and that the nature of factorsand food-web composition may determine the sensitivity level of the system. In a global change scenario,this may have serious and applicable implications for the future of temperate seagrass ecosystems.