The continuous operation of the Three Gorges Reservoir since 2003 has altered the annual runoff into the Changjiang River Estuary, significantly affecting patterns of saltwater intrusion. This has become more pronounced with the development of the East Route of the South-to-North Water Transfer Project, which has changed the runoff distribution and saltwater dynamics once again. Recognizing the critical need to understand these changes, this study employs numerical simulations to investigate the impact of the East Route of the South-to-North Water Transfer Project’s water abstraction on saltwater intrusion in the Changjiang River Estuary post-2003. It assesses intrusion distances, freshwater availability, and periods when water intake might be compromised due to high salinity. Our findings indicate that the East Route of the South-to-North Water Transfer Project markedly influences intrusion patterns. By modeling various runoff scenarios, the study delineates the correlation between average monthly runoff at the Datong Hydrological Survey Station and estuary salinity. It then suggests optimal ecological discharge levels to manage saltwater intrusion effectively. This research provides insights which are necessary for informed water management and ecological protection in the region.