Coastal lagoons are transitional ecosystems that host a unique diversity of species and support many ecosystem services. Owing to their position at the interface between land and sea, they are also subject to increasing human impacts, which alter their ecological functioning. Because coastal lagoons are naturally highly variable in their environmental conditions, disentangling the effects of anthropogenic disturbances like eutrophication from those of natural variability is a challenging, yet necessary issue to address. Here, we analyze a dataset composed of macrobenthic invertebrate abundances and environmental variables (hydro-morphology, water, sediment and macrophytes) gathered across 29 Mediterranean coastal lagoons located in France, to characterize the main drivers of community composition and structure. Using correlograms, linear models and variance partitioning, we found that lagoon hydro-morphology (connection to the sea and lagoon surface), which affects the level of environmental variability (salinity and temperature), as well as lagoon-scale benthic habitat diversity (using macrophyte morphotypes) seemed to regulate macrofauna distribution, while eutrophication and associated stressors like low dissolved oxygen, acted upon the existing communities, mainly by reducing species richness and diversity. Furthermore, M-AMBI, a multivariate index composed of species richness, Shannon diversity and AMBI (AZTI's Marine Biotic Index) and currently used to evaluate the ecological state of French coastal lagoons, was more sensitive to eutrophication (18%) than to natural variability (9%), with nonetheless 49% of its variability explained jointly by both. To improve the robustness of benthic indicators like M-AMBI and increase the effectiveness of lagoon benthic habitat management, we call for a revision of the ecological groups at the base of the AMBI index and of the current lagoon typology which could be inspired by the lagoon-sea connection levels used in this study.