Improving the performance of water use systems (WUSs) is essential for addressing the pressure on water resources for sustainability. Despite the potential impacts of population growth and global warming especially in semi-arid regions, the knowledge and understanding of WUSs and impacts of those main drivers of change on their performance are not available in the Kano River basin (KRB). This paper assesses these impacts on the performance of KRB, using the new and innovative Sefficiency (sustainable efficiency) framework, which incorporates quantity, quality, and beneficial aspects of water use in a comprehensive and systemic manner. We found that performance of the WUSs is sensitive to population growth and global warming under the scenarios considered. Kano River is relatively less sensitive to global warming impacts, while high population growth is dominant. Moreover, their combined effect will result in a reduction of downstream water by 70% and potential demands will far exceed the available supply by 2050. It is recommended that efficient management of water regarding the qualitative as well as quantitative aspects is very critical in KRB. This study can be regarded as the first step, and future studies may adopt the described methodology and can benefit from smart technologies, e.g., sensors and remote sensing.