An ecosystem model of the Minho estuary (NW coast of Iberian Peninsula) was implemented in AQUATOX 3.1 (US-EPA) to check whether the effects of temperature rise, dry years, rainy years and river flow decrease acting isolated (single stressor) or combined (multiple stressor) would induce the same type of response on macroinvertebrate biomass variation and to identify the type of stressor interactions. The model was parameterised with site-specific and species-specific data and accounts for a food web with primary producers, benthic invertebrates, fish and detritus, with 12 biotic groups, 4 groups of detritus and 12 forcing functions.Results showed that macroinvertebrate biomass responded differently to single stressor and multiple stressor scenarios and interactions among the tested stressors were antagonistic. During medium term simulations (∼6 years), the biomass of macroinvertebrate communities from the Minho estuary was maintained or slightly increased in single scenarios of temperature rise but the occurrence of antagonistic interactions between temperature rise, river flow decrease, dry years and rainy years counteracted the increasing tendency in multiple stressor scenarios.Overall, the present results highlight the strong dependence of the system’s biomass and production on hydrodynamics and contribute to increase knowledge on the mechanistic processes behind this. Thus, we recommend an ecosystem-based management of the Minho River basin supported by models such as the present one.