Estuaries are increasingly degraded due to coastal urban development and are prone to hypoxia problems. The macro-tidal Gironde Estuary is characterized by a highly concentrated turbidity maximum zone (TMZ). Field observations show that hypoxia occurs in summer in the TMZ at low river flow and a few days after the spring tide peak. In situ data highlight lower dissolved oxygen (DO) concentrations around the city of Bordeaux, located in the upper estuary. Interactions between multiple factors limit the understanding of the processes controlling the dynamics of hypoxia. Highlights ► A biogeochemical model coupled with a 3D hydrodynamics and sediment transport model was implemented in the Gironde Estuary, accounting for realistic watershed and urban inputs of POC. ► The simulated DO concentrations showed good agreement with field observations and satisfactorily reproduced the seasonal and neap-spring time scale variations around the city of Bordeaux, including summer hypoxia in the upper estuary ► A reduction of POC from sewage overflows would increase the DO minimum in the vicinity of Bordeaux by 3% of saturation, and omitting all wastewater discharge DO would improve by 10% of saturation and mitigate hypoxic events. Abbreviations  DO, dissolved oxygen;  DOC, dissolved organic carbon;  DOM, dissolved organic matter;  NT, neap tide;  POC, particulate organic carbon;  POM, particulate organic matter;  SSC, suspended sediment concentration;  SO, sewage overflow;  ST, spring tide;  TMZ, turbidity maximum zone;  TOC, total organic carbon;