Long-term data series (1971–2015) of physical and biogeochemical parameters were analyzed in order to assess trends and variability of oceanographic conditions in the northern Adriatic Sea (NAS), a mid-latitude shallow continental shelf strongly impacted by river discharges, human activities and climate changes. Interpolation maps and statistical models were applied to investigate seasonal and spatial variability, as well as decadal trends of temperature, salinity, chlorophyll-a and nutrients. This analysis shows that sea surface temperature increased by +0.36% year⁻¹ over four decades. Annual mean flow of the Po River markedly changed due to the occurrence of periods of persistent drought, whereas the frequency of flow rates higher than 3000 m³ s⁻¹ decreased between 2006 and 2015. Moreover, we observed a long-term decrease in surface phosphate concentrations in Po River water (−1.34% year⁻¹) and in seawater (in summer −2.56% year⁻¹) coupled, however, to a significant increase in nitrate concentration in seawater (+3.80% year⁻¹) in almost all seasons. These changes indicate that the nutrient concentrations in the NAS have been largely modulated, in the last forty years, by the evolution of environmental management practices and of the runoff. This implies that further alteration of the marine environment must be expected as a consequence of the climate changes.