The Vu Gia–Thu Bon (VG–TB) river basin is facing numerous challenges to water security, particularly in light of the increasing impacts of climate change. These challenges, including salinity intrusion, shifts in rainfall patterns, and reduced water supply in downstream areas, are of great concern. This study comprehensively assessed the current state of water security in the basin using robust statistical analysis methods such as the Process Analysis Method (PAM), SMART principle, and Analytic Hierarchy Process (AHP). This resulted in the development of a comprehensive assessment framework for water security in the VG–TB river basin. This framework identified five key dimensions, with basin development activities (0.32), the ability to meet water needs (0.24), and natural disaster resilience (0.19) being the most crucial and water resource potential being the least crucial (0.11) according to the AHP methodology. The latter also highlighted 15 indicators, four of which are particularly influential, including waste resources (0.54), flood (0.53), water storage capacity (0.45), and basin governance (0.42). Furthermore, 28 variables with high weight factors were identified. This framework aligns with the UN-Water water security definition and addresses the global water sustainability criteria outlined in Sustainable Development Goal 6 (SDG6). It enables the computation of a comprehensive Water Security Index (WSI) for specific regions, providing a strong foundation for decision-making and policy formulation. It aims to enhance water security in the context of climate change and support sustainable basin development, thereby guiding future research and policy decisions in water resource management.