Bacterial and phytoplankton communities are known to be in close relationships, but how natural and anthropogenic stressors can affect their dynamics is not fully understood. To study the response of microbial communities to environmental and human-induced perturbations, phytoplankton and bacterial communities were seasonally monitored in a Mediterranean coastal ecosystem, Syracuse Bay, where multiple conflicts co-exist. Quali-quantitative, seasonal surveys of the phytoplankton communities (diatoms, dinoflagellates and other taxa), the potential microbial enzymatic activity rates (leucine aminopeptidase, beta-glucosidase and alkaline phosphatase) and heterotrophic culturable bacterial abundance, together with the thermohaline structure and trophic status in terms of nutrient concentrations, phytoplankton biomass (as Chlorophyll-a), and total suspended and particulate organic matter, were carried out. The aim was to integrate microbial community dynamics in the context of the environmental characterization and disentangle microbial patterns related to natural changes from those driven by the anthropic impact on this ecosystem. In spite of the complex relationships between the habitat characteristics, microbial community abundance and metabolic potential, in Syracuse Bay, the availability of organic substrates differently originated by the local conditions appeared to drive the distribution and activity of microbial assemblage. A seasonal pattern of microbial abundances was observed, with the highest concentrations of phytoplankton in spring and low values in winter, whereas heterotrophic bacteria were more abundant during the autumn period. The autumn peaks of the rates of enzymatic activities suggested that not only phytoplankton-derived but also allochthonous organic polymers strongly stimulated microbial metabolism. Increased microbial response in terms of abundance and metabolic activities was detected especially at the sites directly affected by organic matter inputs related to agriculture or aquaculture activities. Nitrogen salts such as nitrate, rather than orthophosphate, were primary drivers of phytoplankton growth. This study also provides insights on the different seasonal scenarios of water quality in Syracuse Bay, which could be helpful for management plans of this Mediterranean coastal environment.