The evolution of rivers and lakes of the Yangtze River and the change of human-water relation since the geological period were reviewed based on historical data, literature and measured data. The human-water relation in the Yangtze River basin has experienced a development process from harmonious coexistence to tension, and to deterioration and then relaxation. Both the Song Dynasty and the founding of P.R.C. characterized by industrialization and urbanization and the period after 2016 featured by the implementation of “great protection rather than great development” saw the turning points of the changes in human-water relation. The target of protecting the Yangtze River is to attain a harmonious coexistence between human and water, and to ensure the free movement in five channels, namely, water and sediment channel, flood discharge channel, navigation channel, ecological channel, and cultural channel. Three criteria for assessing the protection target were expounded as the health aquatic ecosystem of the Yangtze River, the good supporting function of the Yangtze River for human development, and a necessary and sufficient protection to the Yangtze River; the corresponding specific indicators were also given. In addition, the protection target for the current stage is to improve the human-water relation and reduce the negative impacts caused by the imbalance between human and water. Efforts in four aspects should be carried out: solving the problem of flood control safety, improving water environment, accelerating the restoration of water ecology, and ameliorating water culture construction.