<p>Eutrophication and hypoxia are intensifying in many estuarine systems globally, driven by complex interactions between physical and biogeochemical processes. In the Pearl River Estuary (PRE), the combined effects of large-scale river plume dispersion and wind-driven coastal upwelling remain poorly understood and rarely observed at high resolution. To address this gap, we conducted an intensive, high-resolution field campaign in the PRE in June 2021, capturing two contrasting hydrodynamic scenarios: high river discharge with plume-favorable northeasterly winds, and low river discharge with upwelling-favorable southwesterly winds. Using a well-validated three-endmember mixing model, we quantified surface nutrient consumption and bottom nutrient accumulation, and assessed the spatial extent of hypoxia under each scenario. In the high-discharge scenario, strong plume spreading enhanced water column stratification, promoting surface biological consumption of dissolved inorganic nitrogen (DIN) and dissolved inorganic phosphorus (DIP). This resulted in elevated nutrient additions in bottom waters and a hypoxic area covering ∼1232 km². In the low-discharge, upwelling-favorable scenario, the bottom-water hypoxic area contracted to ∼412 km², while low-oxygen waters were brought to the surface and nutrient additions were moderated. Fitted slope values for DIN and DIP additions were 16.4 and 15.1 under the two scenarios, respectively, consistent with the Redfield ratio, indicating organic matter degradation dominated bottom-water nutrient addition and oxygen consumption. Our results reveal the dynamic interplay between river plume dispersion and coastal upwelling in shaping nutrient and dissolved oxygen distributions on intra-seasonal timescales, through coupled physical and biogeochemical processes, including surface primary production and bottom organic matter degradation. These findings provide critical new insights into biogeochemical modeling, coastal environmental forecasting and management.</p>