The Yellow River Basin is a key area for China’s regional development strategy and national ecological security. However, affected by the location, physical environment, and resource endowments, the economic foundation of the region is relatively weak. It has formed an industrial system dominated by energy and heavy chemical industries, which greatly increased the regional ecological burden. The Yellow River Basin is facing the predicaments of weak economic foundation and weak development ability, the pressures of accelerating social and economic development and transformation of development mode, the contradictions between resource use and ecological protection and between industrial development and environmental carrying capacity, and the challenges of deteriorating local living environment. The core contents of ecological environment protection and high-quality development of the Yellow River Basin is to balance the relationship between resource use and environmental protection, the scale of development and the carrying capacity of resources and the environment, and the development of key areas and the protection of the total ecological security to ensure energy security, ecological security, food security, watershed security, and the health of human settlements. We suggest that the region should optimize the industrial development path, actively promote the new industrialization with green industrial development as its core, and improve the level of industrial development and resource and environmental efficiency; optimize the industrial space based on the resource and environmental carrying capacity, determine suitable industrial development space and ecological protection red line, promote the construction of key energy and chemical bases and the construction of industrial clusters in urban agglomerations, implement strict environmental access policies, and improve environmental control standards for industrial development; strengthen spatial control and ecological restoration of energy and mining development projects, and implement a series of regional ecological environment governance and restoration projects.