Abstract. The concentration of oxygen is fundamental to lake water quality and ecosystem functioning through its control over habitat availability for organisms, redox reactions, and recycling of organic material. In many eutrophic lakes, oxygen depletion in the bottom layer (hypolimnion) occurs annually during summer stratification. The temporal and spatial extent of summer hypolimnetic anoxia is determined by interactions between the lake and its external drivers (e.g., catchment characteristics, nutrient loads, meteorology) as well as internal feedback mechanisms (e.g., organic matter recycling, phytoplankton blooms). How these drivers interact to control the evolution of lake anoxia over decadal timescales will determine, in part, the future lake water quality. In this study, we used a vertical one-dimensional hydrodynamic–ecological model (GLM-AED2) coupled with a calibrated hydrological catchment model (PIHM-Lake) to simulate the thermal and water quality dynamics of the eutrophic Lake Mendota (USA) over a 37 year period. The calibration and validation of the lake model consisted of a global sensitivity evaluation as well as the application of an optimization algorithm to improve the fit between observed and simulated data. We calculated stability indices (Schmidt stability, Birgean work, stored internal heat), identified spring mixing and summer stratification periods, and quantified the energy required for stratification and mixing. To qualify which external and internal factors were most important in driving the interannual variation in summer anoxia, we applied a random-forest classifier and multiple linear regressions to modeled ecosystem variables (e.g., stratification onset and offset, ice duration, gross primary production). Lake Mendota exhibited prolonged hypolimnetic anoxia each summer, lasting between 50–60 d. The summer heat budget, the timing of thermal stratification, and the gross primary production in the epilimnion prior to summer stratification were the most important predictors of the spatial and temporal extent of summer anoxia periods in Lake Mendota. Interannual variability in anoxia was largely driven by physical factors: earlier onset of thermal stratification in combination with a higher vertical stability strongly affected the duration and spatial extent of summer anoxia. A measured step change upward in summer anoxia in 2010 was unexplained by the GLM-AED2 model. Although the cause remains unknown, possible factors include invasion by the predacious zooplankton Bythotrephes longimanus. As the heat budget depended primarily on external meteorological conditions, the spatial and temporal extent of summer anoxia in Lake Mendota is likely to increase in the near future as a result of projected climate change in the region.