Spercheios River Basin and the adjacent Maliakos Gulf system (the Aegean Sea) in Central Greece is being examined under a holistic approach that perceives river basins and coastal marine areas as an integrated unit. The main scope is the better understanding of the impacts of the anthropogenic interventions and climate change to the ecological features and hydrochemical and biogeochemical processes taking place in the area. Based on the present study, the interlinkage between Spercheios River’s outflow and Maliakos Gulf is evident in all aspects of the physical environment. Spercheios River is the determining factor of Maliakos Gulf biodiversity and ecological status, due to the high rate of sedimentation that is affecting the geomorphological characteristics of the sea bottom. Moreover, the river’s discharge to the sea is affecting the physicochemical characteristics of the sea water, mainly salinity, especially near the estuaries. Additionally, the impact of anthropogenic activities and interventions are evident on the ecological status of water and sediments of both Spercheios Rivers and Maliakos Gulf samples. Possible climate change will lead to the decrease of precipitation rate and the increase of actual evapotranspiration that will negatively influence the water availability in the Spercheios River Basin. This will directly impact the aquatic ecosystems and Maliakos Gulf hydrodynamics, will affect the spatiotemporal distribution of temperature and salinity, and will inevitably affect the inflows and distribution of nutrients in the sea and the fish fauna composition and populations. An integrated water resource management and adaptive management framework that incorporates the human dimensions into water resource governance is proposed.