Abstract: To enhance the resilience of riparian countries associated with the Lancang-Mekong River (LMR) to drought under a changing environment, there is a pressing need to project future droughts across this river basin. Bias corrected projections from five CMIP6-GCMs under three Shared Socioeconomic Pathways (SSPs) were used as forcing data of a distributed hydrologic model (CREST-Snow) to project future streamflow of the LMR, and to examine meteorological and hydrological droughts across the LMR basin during 2020—2050. The regulation effect of cascade reservoirs on the mainstem of the Lancang River on downstream streamflow in the future was also quantified. Results show that although the entire basin will likely experience an overall wetting trend, the frequency of extreme dry and wet events across the LMR basin is likely to increase during 2020—2050. Droughts will more frequently occur during 2020—2029, as opposed to wet events that will be mainly concentrated during 2030—2050. From a spatial perspective, Laos and Thailand are likely to experience more frequent and severe droughts than other riparian countries. Cascade reservoirs on the Lancang River in China can effectively increase dry-season streamflow in downstream areas (decreasing from 99% in the upper stream to 68% in the downstream), playing a positive and important role in mitigating water shortage during dry seasons or droughts. We advocate for enhancing the cooperation through improving regulation of reservoirs across the entire basin, which should benefit water security and mitigation of droughts for all riparian countries of the LMR.