With the intensification of people’s production and life behaviors, the systemic risks of water, energy and food in the Yangtze River Basin have become increasingly prominent, which has become a bottleneck for sustainable development of social, economic and ecological in the basin. Therefore, studying the symbiotic coordination between water, energy and food is of great significance to promoting regional sustainable development. First, from the perspective of water–energy–food symbiosis, with the water–energy–food ecosystem conceptual model as the nexus, the two-step measurement model of the symbiotic index and the symbiotic level index is used to study the water–energy–food symbiosis of the Yangtze River. Then, we use the BP-DEMATEL-GTCW model to identify the key influencing factors that affect the symbiotic security of the water–energy–food ecosystem. In this research, it is found that the average value of the symbiotic degree of the water–energy–food ecosystem of the 11 provinces or municipalities in the Yangtze River Basin only reached the risk grade. It can also be seen from the identification results of key influencing factors that energy microsystem-related indicators have a greater impact on the symbiotic development of the entire WEF ecosystem. Therefore, special attention needs to be paid to increasing energy sources and reducing expenditure. Relevant departments need to effectively develop primary energy production and expand energy-saving investment through multiple channels to expand energy self-sufficiency and ultimately promote the coordinated and effective development of water, energy and food in the Yangtze River Basin.