Abstract: The study on the vulnerability of water-energy-food-ecology (WEFE) system is of great significance to ensure resource security and ecological security. Based on the pressure-state-response (PSR) framework and the random forest (RF) model, the WEFE vulnerability evaluation index system was constructed. The cross-efficiency data envelopment analysis (CE-DEA) method which considers the combination efficiency of self-evaluation and other-evaluation was used to calculate the vulnerability of the WEFE system of the Yangtze River Economic Belt from 2005 to 2020. The spatiotemporal dynamics were explored using the combined method of a kernel density function and a Kriging interpolation model. Finally, the Tobit model was used to analyze the influencing factors of WEFE vulnerability. The results show that the vulnerability of the WEFE system in the Yangtze River Economic Belt fluctuates. The spatial pattern features “high in the middle and low on both sides”, and the value of vulnerability features middle>East>West. The high-value region of vulnerability is accompanied by a shift towards the northwest. Economic development level, per capita meat production, environmental protection intensity and population density have positive effects on WEFE vulnerability, while industrial structure and technological progress have negative effects.