Salinity gradient energy (SGE) plants generate power from the mixing of salt water and fresh water using advanced membrane systems. In the Strymon River, under low-flow conditions, a salt wedge is formed, developing a two-layer stratified system, which could be used to extract SGE. In this paper, a novel study was implemented by coupling a 3D hydrodynamic model simulating the salt wedge flow, with the SGE model which assesses the net energy produced by a 1 MW SGE plant. Two scenarios were followed: (a) the optimal scenario, operating throughout the year by mixing salt water from the sea (38.1 g/L) and fresh water (0.1 g/L) from the river to produce 4.15 GWh/yr, and (b) the seasonal scenario, utilizing the salinity difference of the salt wedge. Results show that the daily net SGE production varies between 0.30 and 10.90 MWh/day, in accordance with the salinity difference (ΔSsw ~15–30 g/L). Additionally, a retrospective assessment (from 1981 to 2010) of the annual and seasonal net energy production was conducted. This analysis illustrates that the salt-wedge formation (spring to late summer) coincides with the period of increased regional electricity demand. In the future, the emerging SGE could serve as a decentralized renewable energy source, enhancing energy security in the region.