Aquatic ecosystems are under pressure due to human activity. In the summer of 2022, the Odra River (Central Europe) suffered a massive death of fish and mollusks. This paper aims to show selected water quality parameters before and during the ecological disaster and find which parameters may have been crucial to the development of this disaster. We used the Kruskal–Wallis test and Spearman’s correlation to check the water parameters’ spatial and temporal diversification. In addition, non-metric multidimensional scaling was performed. The water quality parameters of the Odra system were analyzed in sections: middle Odra, lower Odra, transitional waters, and Szczecin Lagoon. Human activity has led to the formation of a system with unusual characteristics, disturbing the river’s natural continuum and related processes. The year 2022 in the middle Odra differed from the previous years in having a high water temperature (>24 °C), high ammonium concentrations (>4 mg/L), and relatively low nitrate concentrations (<6.5 mg/L). At the same time, salt pollution in the river was very high (maximum 1.4 g/L). In June and July 2022, we observed low chlorophyll a concentrations in the middle Odra (on average 2.3 µg/L and 4.4 µg/L, respectively), presumably due to salinity stress and high temperatures, suppressing freshwater phytoplankton taxa. This circumstance has created the appropriate conditions for developing euryhaline and thermophilic Prymnesium parvum. Because of decaying organisms, hypoxia occurred in the lower Odra (0.26 mg/L of dissolved oxygen in surface waters), and oxygen conditions worsened in the transitional waters (<4 mg/L). The zonal deaths of fish and mollusks result from multiple stressors induced by human activity. This disaster has proven that it is necessary to improve selected water quality parameters to reduce the risk of such disasters. The most urgent recommendations are to reduce the salt pollution of the upper section of the Odra, reduce nutrient inputs, and improve the condition of smaller rivers feeding the main course of the Odra.