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Grappling with the global ecological concern of the Aral Sea disaster, Uzbekistan exemplifies the urgent necessity of unravelling and addressing the complex Water-Energy-Food-Ecology (WEFE) nexus conflicts in arid regions, a critical task yet largely uncharted. Through the strategic process of 'Indicator Articulation - Weight Calibration - Nexus Coordination Quantification - Correlational Analysis', this work has developed a tailored framework that integrates a novel, context-specific indicator system, enabling an illumination of the intricate dynamics within the WEFE nexus in arid regions. During 2000–2018, the WEFE Nexus in Uzbekistan showed low-level coordination, indicating systemic imbalances. The Aral Sea crisis was the central disruptor, resulting in a moderately disordered ecological subsystem. Concurrently, disorder was observed in water resources, signaling inadequate management and potential overutilization. Furthermore, Coordination for energy and food were barely coordinated and under primary coordination respectively, underlining critical challenges in energy efficiency and food security. Over the last two decades, the WEFE Nexus has evolved towards a tighter interlinkage, yet the stability of this coupling coordination has experienced increased fluctuations, indicating that Uzbekistan's policies in the WEFE subsystems have been less stable in the last two decades and are in need of further adjustment and improvement. To address the challenges, we recommend a comprehensive approach that integrates technological, infrastructure, and policy solutions is needed. Specifically, promoting water-saving irrigation technology, renewing and maintaining outdated energy facilities, and raising public awareness of ecological protection are part of the essential measures. Furthermore, alleviating the contradiction between economic growth and ecological conservation remains a major challenge. Collectively, our constructed WEFE Nexus framework, with its extendable and context-specific indicators, holds significant potential for broad application in the analysis of multi-sectoral sustainability, particularly within arid regions globally, and forms a solid foundation for the formulation of effective, targeted policies and sustainable development strategies. [Display omitted] • Developed an integrative framework with specific indicators for UZB's WEFE Nexus. • The synergistic Nexus and CCDM effectively identify critical sustainability indexes. • The ecological crisis evidences human pressure on ecosystems in Uzbekistan. • Nexus interactions: 28% trade-offs, 35% synergies, emphasizing synergy potential. [ABSTRACT FROM AUTHOR]