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The hypoxic zone in the northern Gulf of Mexico is among the most dramatic examples of impairments to aquatic ecosystems. Despite having attracted substantial attention, management of this environmental crisis remains challenging, partially due to limited monitoring to support model development and long‐term assessments. Here, we leverage new geostatistical estimates of hypoxia derived from nearly 150 monitoring cruises and a process‐based model to improve characterization of controlling mechanisms, historic trends, and future responses of hypoxia while rigorously quantifying uncertainty in a Bayesian framework. We find that November–March nitrogen loads are important controls of sediment oxygen demand, which appears to be the major oxygen sink. In comparison, only ~23% of oxygen in the near‐bottom region appears to be consumed by net water column respiration, which is driven by spring and summer loads. Hypoxia typically exceeds 15,600 km2 in June, peaks in July, and declines below 10,000 km2 in September. In contrast to some previous Gulf hindcasting studies, our simulations demonstrate that hypoxia was both severe and worsening prior to 1985, and has remained relatively stable since that time. Scenario analysis shows that halving nutrient loadings will reduce hypoxia by 37% with respect to 13,900 km2 (1985–2016 median), while a +2°C change in water temperature will cause a 26% hypoxic area increase due to enhanced sediment respiration and reduced oxygen solubility. These new results highlight the challenges of achieving hypoxia reduction targets, particularly under warming conditions, and should be considered in ecosystem management. [ABSTRACT FROM AUTHOR]