The combination of ongoing climate change and the historical loss of streams and wetland areas have presented new ecological challenges. These challenges became evident during a massive fish kill in Lake Fil, Denmark, in August 2018. We know that high amounts of labile organic matter entered the lake after a particularly heavy rainfall that followed a long period of heat and drought. Bacteria decomposed the organic matter, resulting in a quickly deoxygenated lake and an extensive fish kill. However, we do not know whether there is spatial variation in the amount of transportable labile matter across the catchment area. Identifying catchment ‘hotspots’ that sustain particularly high oxygen consumption rates will help managers to pursue interventions that can promote a high ecological quality of Lake Fil and its catchment. The method we developed to identify hotspots can be used by practitioners everywhere to prepare for and mitigate events similar to the 2018 disaster at Lake Fil. To identify hotspots in the stream network that feeds into Lake Fil, we measured oxygen consumption rates and environmental variables at 13 sites on five occasions. We found that oxygen consumption rates varied 2–16-fold between sites and 2–13-fold between sampling days. Oxygen consumption rates were positively related to the concentration of tryptophan-like material and ammonium but negatively related to the complexity of humic substances. Together, these variables accounted for 65% of the variation in the oxygen consumption rate across sub-catchments. High levels of tryptophan-like material and dissolved nutrients derive from intensive agricultural land use in the catchment. However, all oxygen consumption rates measured in this paper were apparently lower than those during the fish kill of August 2018, when the catchment fed higher concentrations of labile organic matter into the lake. The risk of anoxic water and fish kills can be mitigated by reducing and dispersing the input of labile organic matter following shifting periods of drought and heavy rain, which can be done by creating wetlands in the stream network or by implementing biogas facilities, thereby reducing pulses of organic matter and nutrients entering the stream.