In view of multidimensional interwoven characteristics of water problems in the Guangdong-Hong Kong-Macao Greater Bay Area, this study summarized the structures of five technically controllable and logically related water security regulation and control subsystems, including river regime control subsystem, inland waters environment and ecology regulation subsystem, outer river salt tide regulation subsystem, urban rainstorm and flood regulation subsystem, and outer river flood tide regulation subsystem, and discussed key mechanisms of the subsystems, the principle and key technologies for collaborative requlation, and the collaborative model algorithm framework. Then a theoretical framework of water security collaborative regulation and control in the Guangdong-Hong Kong-Maca Greater Bay Area was constructed. As a case study, the water security collaborative regulation and control theory was applied to Pearl River Estuary, providing new solutions for the systematic management of water problems in this area.