Hypoxia is increasing in coastal oceans due to high oxygen consumption and weak ventilation. Quantifying biological oxygen uptake and how its effects on hypoxia respond to stratification is important for management and predicting future trends. This work introduces a simple analysis to quantify and compare the biological and physical drivers of hypoxia, by using an example from the Pearl River Estuary (PRE) region (10–70 m deep). We show that in the PRE region, sediment respires ∼50 % of organic matter produced in the water column and oxidizes ∼88 % of the ammonium produced from sediment organic matter degradation. These processes lead to high sediment oxygen uptake (SOU; 41.1 ± 16.3 mmol m-2d-1). Under stratification, sediment's effect on the bottom oxygen is strongly regulated by the thickness of the bottom boundary layer (BBL), and the robust relationships can be used to parameterize SOU. We then construct a simple and generic mass-balance model to estimate the water column oxygen uptake in the BBL (WOUBBL) and quantify the total oxygen loss. By comparing model results to observations in the PRE and other similar systems, we show that the sensitivity of oxygen levels to SOU is largely controlled by the duration of stratification, while the organic matter settling velocity controls the contributions of SOU to total oxygen consumption. We further demonstrate how the model can help evaluate the primary drivers of hypoxia (stratification versus high oxygen consumption), determine the time scale of stratification required to develop hypoxia, and explain the within and across system variabilities.