© 2020, The Author(s). Climate change currently affects the resilience and aquatic ecosystem. Climate change alters rainfall patterns which have a great impact on river flow. Annual flooding is an important hydrological characteristic of the Mekong River Basin (MRB) and it drives the high productivity of the ecosystem and biodiversity in the Tonle Sap floodplain and the Mekong Delta. This study aims to assess the impacts of climate change on river flow in the MRB and flood inundation in the Lower Mekong Basin (LMB). The changing impacts were assessed by a two-dimensional rainfall-runoff and inundation model (RRI model). The present climate (1979–2003) and future projected climate (2075–2099) datasets from MRI-AGCM3.2H and MRI-AGCM3.2S models were applied with a linear scaling bias correction method before input into the RRI model. The results of climate change suggested that flood magnitude in the LMB will be severer than the present climate by the end of the twenty-first century. The increment of precipitation between 6.6 and 14.2% could lead to increase extreme flow (Q5) 13–30%, peak inundation area 19–43%, and peak inundation volume 24–55% in the LMB for ranging of Representative Concentration Pathways (RCP) and sea surface temperature (SST) scenarios while there is no significant change on peak flood timing. [Figure not available: see fulltext.]