The Sittaung river basin (SRB) remains one of the least studied basins of Myanmar in terms of the assessment of the impact of climate change. As several reservoirs already exist in the basin, much research is needed to understand how projected climate change impacts rainfall, temperature, flows, domestic and agricultural demands, and hydropower generation. Given the limitation in observed data on the ground, a combination of satellite-derived meteorological data and digital elevation data is used to generate inputs to a Water Evaluation and Planning (WEAP) model. Five CMIP5 GCMs are used in the WEAP to assess the impact of climate change on the water, food, and energy production of the SRB for the baseline (BL: 1985–2014), near future (NF: 2021–2050), and far future (FF: 2051–2080) periods. The results indicate that the average temperature and rainfall are likely to increase in the future for the SRB. December and January are expected to be drier and warmer, whereas rainy months are expected to be wetter and warmer in the future. The BL flows (1091 m3/s) are expected to increase by 7–10% during NF and by 16–19% during FF at the basin outlet. Meanwhile, the unmet domestic demand during BL (1.3 MCM) is expected to decrease further by approximately 50% in the future. However, the unmet agricultural demand (667 MCM) for food production is estimated to increase from the BL by 11–15% during NF and by 14–19% during FF. Similarly, the total energy generation of nine hydropower projects (4.12 million MWh) is expected to increase by 9–11% during NF and by 16–17% during FF. Thus, the riverine flows are expected to increase in the future, thus positively impacting the domestic and hydropower sectors, whereas the unmet demands in the agricultural sector likely remain unsatisfied. These results will help the water, agriculture, and energy sectors to develop strategies to maximize benefits and cope with the impacts of climate change in the near and long-term future.