Both the distance between the upstream and downstream cities and the capacity of urban water infrastructure would affect the water safety of the cities in the catchment. In this work, the concept of safe distance for urban growth was proposed. If the water quality between the upstream and the downstream cities can meet the functional requirements of the water environment, then the distance between the upstream and the downstream cities is safe. Taking two neighboring cities in the Yangtze River catchment as a case study, a distributed Cellular Automata (CA) model and a backpropagation (BP) neural network water quality model were used to discuss the safety distance between the two cities. The results provided some decision-making on urban sprawl control and rational urban development.