The evaluation of the hydrography and biogeochemistry of the Adriatic Sea over the last century was summarized in this review to point out any changes in river runoff and provide an overview of the cause and effect of these trends on marine ecosystems. Although several rivers flow into the Adriatic, the most affected area is the northern Adriatic, where the Po River loads into the basin half of the total freshwater input, carrying river runoff and causing algal blooms and hypoxia phenomena. These fresh waters of the northern Adriatic flow predominantly along the entire western side, reaching the southernmost part of the basin up to the Mediterranean Sea. Here, and in the whole basin, variations in river runoff and nutrient concentration have been observed through the years. Starting from 1960 until the end of the century, an increase in nutrient discharge and phytoplankton activity was reported, with negative repercussions on local fisheries, species richness, and recreational activities within the basin. However, a recent decrease in river inflow has been observed along the coastal belt, which can trigger negative consequences for the food web of the marine ecosystem. These trends, more broadly, corroborate the vulnerability of the Adriatic Sea and stress the importance of implementing strategies for the defense of the relevant ecosystems within its confines.