The Nam Ngum River Basin (NNRB) in Laos has received attention of foreign investors due to high hydropower development potential and low per capita electricity consumption. The NNRB is rapidly developing due to its hydropower generation potentials while water demands will increase for agricultural and domestic purposes due to population increase and land-use changes. Water availability conditions will be affected with the increasing water demand and climate change may worsen the water availability conditions. Climate is often defined as the weather averaged over time whereas weather describes atmospheric conditions at a particular place and time in terms of air temperature, pressure, humidity, wind speed and rainfall. On regional scale, climate change impact assessment is crucial for water resource planning, management and decision making. First part of this study, reliable estimation of climatic variables is performed under climate change. Second part assess the changes in water resources regimes and sustainability conditions of agricultural and domestic water user sectors under climate change for “do nothing” option that are critical for strategic planning and to minimize the negative impacts. Third part assesses the long-term climate change trends, water allocation challenges and appropriate adaptation measures to minimize watershed impacts to achieve sustainability and long-term management goals. The major findings of this study shows (1) wetter and warmer climates especially in the latter part of the century indicating less water availability, (2) sustainability in meeting the water demands for agriculture and domestic use is affected under “do nothing” option, and (3) watershed scale adaptation measures improve the (1) hydropower generation, (2) sustainability conditions in agricultural and domestic water user sectors, and (3) flow regimes.