The spatial extent of summertime low-oxygen waters in the Pearl River Estuary (PRE) has significantly expanded in recent decades. Yet, a quantitative understanding of the long-term trends, interannual variability and underlying drivers of low-oxygen conditions in the PRE is still lacking. To that end, we conducted a comprehensive investigation using long-term (1994-2018) monthly observations off Hong Kong waters on the eastern side of PRE and numerical simulations from a coupled physical-biogeochemical model. Observations showed a significant summer deoxygenation trend in the coastal waters off Hong Kong over the past 25 years. Multiple regression analysis revealed that both the wind speeds and concentrations of dissolved inorganic nitrogen (DIN) played a significant role in determining the interannual variations (by 39% and 49%, respectively) and long-term trends (by 39% and 56%, respectively) of the spatial extent and intensity of the low-oxygen conditions off Hong Kong waters. Consistent with the observed deoxygenation trend, the model simulation revealed an expansion of low-oxygen waters in the entire PRE from 1994 to 2018. A series of sensitivity tests were conducted to further discern the relative contributions of wind speed, freshwater discharge and nutrient input to the long-term changes of oxygen levels at different subregions of PRE. Results showed that low-oxygen conditions in the western PRE were markedly influenced by terrestrial input of organic matter and inorganic nutrients. On the contrary, the expanding low-oxygen waters in the eastern PRE were mainly attributed to the increased nutrient loading and the altered physical forcings (e.g., the long-term decreasing trend in wind speeds and freshwater discharge) that created favorable biophysical conditions for the excessive production of marine-sourced organic matter. Changes in physical environment could offset the potential benefits of nutrient management, suggesting that more stringent nutrient reduction strategies are required to mitigate the deteriorating low-oxygen conditions in the PRE.