Low dissolved oxygen (DO < 4 mg/L) plays a crucial role in shaping the nutrient cycle in tidal rivers and affects nutrient flux into the ocean. However, it often garners less attention compared to low DO in coastal waters. In this study, a water quality model alongside observations was employed to study the driving forces of low DO in the intricate tidal rivers of the Pearl River Delta (PRD), which is characterized by intensive anthropogenic activities and variable hydrological processes. Both observations and model results reveal that low DO occurs in the tidal rivers around densely populated cities during summer. Longer residence time exists in narrow tributaries around cities with heavy pollution, which makes these regions prone to developing low DO. Oxygen budget analysis reveals that DO dynamics are modulated by seasonal hydrological processes and water temperature, making the tidal rivers develop low DO. Oxidation of Carbonaceous Biochemical Oxygen Demand (CBOD) dominates the DO depletion processes, followed by nitrification and sediment oxygen demand (SOD). Numerical experiments show that NPS loading predominates DO consumption, leading to intermittent low DO during rain events in Dongguan. Conversely, in areas encompassing Guangzhou, Foshan, and Jiangmen, PS loading exerts a greater influence, resulting in persistent low DO throughout the summer. This study lays a foundational understanding of DO dynamics within the tidal rivers of the PRD, offering valuable insights into the region’s aquatic environment management. The findings serve as a critical resource for stakeholders involved in safeguarding the ecological health of the PRD’s waterways.