The Mediterranean Sea ranks among the most overexploited and fastest-warming ocean regions. This situation calls for urgent development of global change scenarios and models of marine biodiversity to anticipate changes and support ecosystem-based management strategies across the entire Mediterranean Sea. Using a new end-to-end modelling chain for the whole Mediterranean Sea, we explored the potential effects of changes in fishing pressure on marine resources and ecosystem structure and functioning under a worst-case climate change scenario (RCP8.5). We found that a decrease in fishing mortality or an improvement in fishing selectivity could increase the total biomass and total catch of high trophic level species by the middle and end of the 21st century, especially the biomass of demersal, large pelagic and benthic species, thereby reversing the projected climate-induced decrease in their biomass and catch by the end of the century in the western Mediterranean basin. In contrast, climate change could offer opportunities for some eastern Mediterranean fisheries to increase catches of thermophilic and/or exotic species benefiting from new favourable environmental conditions. Based on a suite of ecological indicators, our results indicated clear positive effects of a more sustainable fisheries management on ecosystem structure and functioning. However, a decrease in fishing pressure may not fully compensate for climate-induced changes on marine resources and ecosystems, but rather buffer some projected negative impacts. Our study highlights the need for a more sustainable exploitation of fisheries resources to restore marine ecosystems and increase their resilience in a global change context.