This study assesses the seasonal regulation of river discharge by hydropower dam-induced cascade reservoirs in the Lancang River and its effect on downstream freshwater and estuarine saltwater intrusion. There are eight main reservoirs in the Lancang River, with a total regulation capacity of 25.67 billion m3, which regulates river discharge by conserving water in the flood season and releasing water in the dry season. River discharge during the dry season from 1960 to 2009 accounted for 21% of the annual discharge before the cascade reservoirs were constructed and increased to 33% from 2010 to 2015 after the cascade reservoirs were constructed at the Jinghong hydrological station, which is the lowermost station in the Lancang River. During the 2016 extreme drought in the lower Mekong River basin, the river discharge increased by 550, 367, 1283, 969, and 524 m3/s in January, February, March, April, and May, respectively, regulated by the cascade reservoirs at the Jinghong hydrological station. Considering runoff, tides, wind, and continental shelf currents, a high-resolution three-dimensional numerical model was used to simulate the effect of regulation of river discharge by the cascade reservoirs in the Lancang River on the saltwater intrusion in the Mekong River Delta (MRD). The simulation results show that the seasonal regulation of river discharge by the cascade reservoirs in the Lancang River weakens estuarine saltwater intrusion during the dry season, especially in the sand bar areas, which is much more significant in the extreme dry season of 2016. The seasonal regulation of river discharge by the reservoirs in the Lancang River makes the seasonal distribution of downstream river discharge more uniform, favoring downstream freshwater utilization and alleviating flood disasters and saltwater intrusion in the MRD.