The uncertainty of water resource availability poses a significant challenge to the sustainable development. In this study, a scenario-based optimization model is developed for the integrated management of the water-ecology-energy-food (WEEF) nexusWater-ecology-energy-food nexus. The model is applied to the Jiziwan AreaJiziwan Area of the Yellow River, where 27 scenarios are designed to address uncertainty of water resource availability. Results indicate that: (i) compared to the current situation, the proportion of surface water would decrease from 68.7 to 48.4%, and the proportion of groundwater would decline from 25 to 16.4% following WEEF optimization, which underscores the urgent need to diversify water sources to mitigate over-exploitation of traditional resources; (ii) with increased water availability, the water allocation for agriculture and resident would rise, reflecting the influence of resource uncertainty on water allocation pattern; (iii) among all water users, agriculture would remain the primary consumer, experiencing a decline in water allocation ranging from 16.4 to 20.3% compared to the current situation; ecology would be the second-largest water user and its water allocation would increase by 11.4–14.1%. The results indicate a positive shift toward environmental restoration and the sustainable development of the WEEF nexus, which can help decision-makers make informed decisions.