This study investigates over 30 years of dissolved oxygen dynamics in the deep interior of Lake Constance (max. depth: 250 m). This lake supplies approximately four million people with drinking water and has undergone strong re-oligotrophication over the past decades. We calculated depth-specific annual oxygen depletion rates (ODRs) during the period of stratification and found that 50% of the observed variability in ODR was already explained by a simple separation into a sediment- and volume-related oxygen consumption. Adding a linear factor for water depth further improved the model indicating that oxygen depletion increased substantially along the depth. Two other factors turned out to significantly influence ODR: total phosphorus as a proxy for the lake’s trophic state and mean oxygen concentration in the respective depth layer. Our analysis points to the importance of nutrient reductions as effective management measures to improve and protect the oxygen status of such large and deep lakes.