Southeast Asia, in general, and the Mekong Basin (MB), in particular, with its typically warm and wet climate, face water resource challenges. A deep understanding of the future streamflow is needed to manage water resource successfully. Data scarcity and topographical differences have made it difficult to accurately reproduce the streamflow regime in the sub-catchment of the MB. The main goal of this study was to provide the first assessments of streamflow impacts due to climate change for the Nam Ou Basin, a primary Lao sub-catchment of the MB, employing the most updated Couple Model Intercomparison Project Phase 6 (CMIP6) climate scenarios. The MIKE-NAM (Nedbor Affstromnings Model), the observed hydro-meteorological data, and the Moderate Resolution Imaging Spectroradiometer (MODIS) evaporation were employed. The climate change scenarios showed increases in seasonal and annual river discharges with different magnitudes in the future. The annual streamflow was expected to rise by 0.31%, 16.75%, and 38.31% in the 2040s as well as 23.35%, 32.80%, and 74.82% in the 2080s under three scenarios, respectively. The wet season in the Nam Ou Basin occurs one month earlier. The wet season flows increased by 5.6% – 76.9%, and the dry season flow showed a contrasting directional change, decreased by 8.4%. The annual peak discharge also exhibited an increase of 3.2%–14.6% for the SSP1-1.9 scenario in the mid-century (the 2040s), and end-century (2080s). Those figures are 8.9–19.7% for the SSP2-4.5, and 23.3–48.9% for the SSP5-8.5 scenario, respectively. The study revealed the streamflow variation under the effect of climate change in the Nam Ou Basin, a sub-catchment of the MB, highlighting the need for special consideration in disaster risk mitigation, especially under climate change.