This study presents hydrological impacts of future climate change (CC) and land use/cover change (LUCC) for the Srepok River Basin (SRB) in the Vietnam’s Central Highlands. The hydrology cycle of this basin was reproduced using Soil and Water Assessment Tool (SWAT) allowing an evaluation of hydrological responses to CC and LUCC. Future climate scenarios of the 2015–2100 period under Representative Concentration Pathways (RCP) 4.5 simulated by five General Circulation Models (GCMs) and LUCC scenario in  2050 were developed. Compared to the reference scenario (1980–2005), future LUCC increases the streamflow (0.25%) and surface runoff (1.2%) and reduces the groundwater discharge (2.1%). Climate change may cause upward trends in streamflow (0.1 to 2.7%), surface runoff (0.4 to 4.3%), and evapotranspiration (0.8 to 3%), and a change in the groundwater discharge (− 1.7 to 0.1%). The combination of CC and LUCC increases the streamflow (0.2 to 2.8%), surface runoff (1.6 to 5.6%), and evapotranspiration (1.0 to 3.1%), and reduces the groundwater discharge (1.5 to 2.7%) with respect to the reference scenario. Moreover, the results noted that the water scarcity may happen in the dry-seasonal months.