With the growing influences of anthropogenic activities and climatic change, the problem concerning the vulnerability of the Water-Energy-Food-Carbon (WEFC) system in the Yellow River Basin is prominent. Using the VSD framework, the WEFC system vulnerability evaluation index system was constructed with 60 cities in the Yellow River Basin as the samples, and the WEFC system vulnerability of each city was measured from 2010 to 2019. Kernel density estimation, Theil index, and spatial correlation analysis were employed to investigate spatio-temporal evolution characteristics. Geodetector was utilized to analyze the driving factors of WEFC system vulnerability. The results demonstrate that: (1) The vulnerability of the WEFC system in the Yellow River Basin tends to decrease, with a spatial pattern of “low in the middle and high on both sides”; the vulnerability is largest in the upper and lower reaches, while smallest in the middle reaches. (2) The spatial difference in vulnerability narrows in the middle and lower reaches, while expanding in the upper reaches. The differences among the three major regions mainly originate from within the region, with the upper reaches having the largest difference and contribution; the vulnerability is featured with a significant spatial correlation, with the upper and lower reaches cities mostly displaying a “high-high” agglomeration and the middle reaches mainly showing a “low-low” one. (3) Factors, including the carbon and ecological carrying capacity coefficient, water resource development and utilization rate, and urbanization rate, mainly influence the WEFC system vulnerability; the spatial heterogeneity of core drivers at the regional scale is obvious, with the upper reaches regions being more strongly influenced by factors of the water resources system, while the middle and lower reaches regions are more sensitive to factors concerning industrial pollution of the energy subsystem. The explanatory power of carbon ecological carrying capacity reaches its peak in the middle reaches. The interaction of factors increases the strength of the impact on vulnerability. This study provides decision support and policy suggestions for achieving a balanced and coordinated development of water resource utilization, energy development, food production, and carbon cycle system in the Yellow River Basin. Investigating WEFC system vulnerability to support SDG 11 provided valuable insights and policy strategies for building cities that are inclusive, secure, resource-efficient, and resilient in the face of climate change and disaster risks.