The Bui hydropower plant plays a vital role in the socio-economic development of Ghana. This paper attempt to explore the combined effects of climate-land use land cover change on power production using the (WEAP) model: Water Evaluation and Planning system. The historical analysis of rainfall and stream flow variability showed that the annual coefficient of variation of rainfall and stream flow are, respectively, 8.6% and 60.85%. The stream flow varied greatly than the rainfall, due to land use land cover changes (LULC). In fact, the LULC analysis revealed important changes in vegetative areas and water bodies. The WEAP model evaluation showed that combined effects of LULC and climate change reduce water availability for all of demand sectors, including hydropower generation at the Bui hydropower plant. However, it was projected that Bui power production will increase by 40.7% and 24.93%, respectively, under wet and adaptation conditions, and decrease by 46% and 2.5%, respectively, under dry and current conditions. The wet condition is defined as an increase in rainfall by 14%, the dry condition as the decrease in rainfall by 15%; current account is business as usual, and the adaptation is as the efficient use of water for the period 2012–2040.