Amidst global climate change, the processes of urbanization and population growth have placed immense pressures on water resources. To this point, there has been limited research on long-term spatiotemporal evolution within this context. The Guangdong-Hong Kong-Macao Greater Bay Area, currently one of China’s three major urban clusters, has employed the City-Water System Relationship (CWSR) methodology to explore the progression of its cities from early human settlements to the Qing Dynasty. Utilizing ArcGIS software to depict the spatial relationships between urban areas and water, the study significantly highlights the connections between river systems and urban patterns, as well as the impacts of water systems, environmental heterogeneity, and the political and economic factors influencing urban development. The findings also, to some extent, represent the historical concentration of economic centers in the Guangdong-Hong Kong-Macao Greater Bay Area and reveal the intensity of human activities in regional development.