Low oxygen concentrations in lakes and reservoirs are an ongoing environmental concern, particularly in light of increasing anthropogenic activity and climate change. Oxygen depletion processes in lakes are still not completely understood and a variety of models have been proposed based on limited field observations. Here, we present field measurements of oxygen depletion processes in a deep lake, Lake Geneva (Switzerland). The aim of this study was to quantify three basic processes controlling hypolimnetic oxygen depletion and their relative contribution to the total oxygen depletion (TOD) rate. Sediment oxygen uptake (SOU) and the flux of reduced substances were estimated based on oxygen microprofile measurements and sediment core data of reduced substances. Acoustic Doppler current profiler measurements and hydrodynamic modeling were used to ensure that SOU was measured under typical hydrodynamic conditions. Comparison with long-term monitoring data allowed for an estimate of the relative importance of SOU and water column mineralization (WCM). Results show a decrease in both SOU and WCM down to mid-depth which could not be explained by changes in hydrodynamic conditions or temperature. Below mid-depth, TOD increased due to an enhanced sediment area to water volume ratio (α). This vertical pattern of oxygen depletion is driven by (1) lake morphometry paired with increasing α, and (2) decreasing organic matter mineralization in the water column with depth. The findings are explained by a model which separates the oxygen depletion into an exponentially decreasing component, representing the fast-decaying fraction of the organic matter, and a constant background component.