The vulnerability of the water-energy-food-ecology nexus in the Yangtze River Economic Belt greatly impacts regional sustainable development. This study aimed to conduct a quantitative assessment and temporal and spatial evolution analysis of the vulnerability of the water-energy-foodecology nexus in the Yangtze River Economic Belt from 2008 to 2018 and diagnose the main factors that hinder the vulnerability reduction. Firstly, the vulnerability assessment index system was constructed according to the Vulnerability-Scoping-Diagram framework. Then, SPA-TOPSIS and ArcGIS10.7 were comprehensively used to evaluate the vulnerability of the water-energy-food-ecology nexus. Finally, the obstacle degree model was used to diagnose the main factors that hinder the vulnerability reduction of the water-energy-food-ecology nexus from the index and subsystem levels. The results showed that the vulnerability level of the water-energy-food-ecology nexus in the Yangtze River Economic Belt decreased from 2008 to 2018, and the overall trend was improved. The vulnerability level of the upstream region was generally lower than that of the middle and lower reaches. The main obstacles are the comprehensive utilization rate of solid waste, the primary industry energy consumption ratio, energy consumption intensity, water consumption per 10,000-yuan GDP, domestic water consumption per capita and fertilizer application per unit grain sowing area. The energy subsystem is the primary obstacle system, followed by the food, ecology, and water subsystem.