A mechanistic model was developed to predict midsummer bottom-water dissolved oxygen (BWDO) concentration and hypoxic area on the Louisiana shelf of the northern Gulf of Mexico, USA (1985–2011). Because of its parsimonious formulation, the model possesses many of the benefits of simpler, more empirical models, in that it is computationally efficient and can rigorously account for uncertainty through Bayesian inference. At the same time, the model incorporates important biophysical processes such that its parameterization can be informed by field-measured biological and physical rates. The model is used to explore how freshwater flow, nutrient load, benthic oxygen demand, and wind velocity affect hypoxia on the western and eastern sections of the shelf, delineated by the Atchafalaya River outfall. The model explains over 70% of the variability in BWDO on both shelf sections, and outperforms linear regression models developed from the same input variables. Model results suggest that physical factors (i.e., wind and flow) control a larger portion of the year-to-year variability in hypoxia than previously thought, especially on the western shelf, though seasonal nutrient loads remain an important driver of hypoxia, as well. Unlike several previous Gulf hypoxia modeling studies, results do not indicate a temporal shift in the system's propensity for hypoxia formation (i.e., no regime change). Results do indicate that benthic oxygen demand is a substantial BWDO sink, and a better understanding of the long-term dynamics of this sink is required to better predict how the size of the hypoxic zone will respond to proposed reductions in nutrient loading.