In semi-arid regions, where hydrological resources are very vulnerable and where there are water shortages in many regions of the world, it is of great importance to assess the vulnerability that a system is facing or will face to the potential impacts of climatic changes and changes on the use of land. For that reason, this research focuses on evaluating the global vulnerability of a hydrological basin, taking into consideration these changes. Being different from the existing methodologies that assess the vulnerability, our methodology interconnects through a new interface a distributed hydrological model, global climate models, climate change scenarios, land use change scenarios and the largest number of system variables calculated with information from official sources. Another important point of our methodology is that it quantifies the global vulnerability of the system, taking into consideration hydrological, environmental, economic and social vulnerabilities. The results obtained show that the proposed methodology may provide a new approach to analyze vulnerability in semi-arid regions. Moreover, it made it possible to diagnose and establish that the greatest current and future vulnerabilities of the system are the result of activities in agricultural areas and urban centers.