Global estuarine hypoxia is among the most acute environmental issues, and the Changjiang Estuary (CE) is well known as one of the largest estuarine hypoxic systems. However, the physical-biogeochemical mechanisms controlling the spatial variability and heterogeneity of summer hypoxia have been rarely examined in this region. Based on observational data, the essential linkages between physical-biogeochemical processes and spatial variability of hypoxia were revealed off the CE. The hypoxia generally occurred in a transitional region off the CE, presenting to be spatially variable and heterogeneous in its distribution and intensity. The river plume, stratification, front, upwelling and localized high phytoplankton biomass combine to shape the spatial morphology and scope of hypoxia. Notably, a pronounced intermediate-layer hypoxic plume was observed to expand offshore from the bank slope area off the CE. It was bounded by a pycnocline and connected to the seafloor near the foot of bottom front, and a secondary circulation and associated physical-biogeochemical processes are suggested to regulate this unique hypoxic plume. Moreover, the co-occurrence of offshore detached diluted water plume and hypoxia also existed in the northeastern area off the CE, and we demonstrate that the surface patchness of phytoplankton bloom induced by the offshore detached CDW plume may contribute to the formation of this local hypoxia. The findings would considerably contribute to our understanding of the spatially variable hypoxia in river plume-upwelling-front coupled estuarine systems, providing a sound basis for prediction and simulation under anticipated future conditions.