The Yangtze River, the largest river in China, has been facing major challenges in massive flooding and eco-environmental health over the past decades. Sustainable socioeconomic development in the Yangtze River Basin depends on water and ecosystem security. This overview addresses eco-water security under the changing environment of the Yangtze River Basin. Looking forward to a healthy Yangtze River in the future, there are still uncertainties regarding how to assess and wisely manage the Yangtze River through a systematic, integrated approach applied to multiple dimensions, water, biodiversity, ecological services, and resilience, for the sustainable development of ecosystems and human beings. The Yangtze Simulator, an integrated river basin model powered by artificial intelligence and interdisciplinary science, is introduced and discussed, and it will serve as a robust tool for good governance of the Yangtze River Basin.