Facing the problems of frequent salt intrusion disasters, river water drought and increasing demand for water supply in the Guangdong-Hong Kong-Macao Greater Bay Area (GBA), situation of salt intrusion and the dominant problems of Pearl River Estuary is analyzed systematically, and the movement mechanism and upward trend of salt tide in Pearl River Estuary are revealed. Combined with the characteristics of spatiotemporal distribution of water resources and the patterns of water intake, storage and supply, a new comprehensive prevention and control system of saltwater intrusion in GBA is created with comprehensive consideration of the three-level measures, These three-level measures consist of upstream water replenishment to press saltwater, midstream water storage to avoid saltwater, and downstream engineering measures to prevent saltwater.