Nowadays, the Mediterranean freshwater systems face the threat of water scarcity, along with multiple other stressors (e.g., organic and inorganic contamination, geomorphological alterations, invasive species), leading to the impairment of their ecosystem services. All these stressors have been speeding up, due to climate variability and land cover/land use changes, turning them into a big challenge for the water management plans. The present study analyses the physicochemical and phytoplankton biomass (chlorophyll-a) dynamics of a large reservoir, in the Mediterranean region (Alqueva reservoir, Southern Portugal), under diverse meteorological conditions and land cover/land use real scenarios (2017 and 2018). The most important stressors were identified and the necessary tools and information for a more effective management plan were provided. Changes in these parameters were further related to the observed variations in the meteorological conditions and in the land cover/land use. The increase in nutrients and ions in the water column, and of potentially toxic metals in the sediment, were more obvious in periods of severe drought. Further, the enhancement of nutrients concentrations, potentially caused by the intensification of agricultural activities, may indicate an increased risk of water eutrophication. The results highlight that a holistic approach is essential for a better water resources management strategy.