The shrinkage of some cities has a certain impact on the sustainable development of the Yangtze River Economic Belt. Based on the population census and statistical data, this paper takes 110 cities in the Belt as the objects, identifies the shrinking cities in the Belt, and compares the development indicators of the main economic and social fields between the shrinking cities and the non-shrinking ones. Furthermore, it takes advantage of the “center-periphery” model and the data of commuting time to discuss the spatial mechanism of the change of urban population scale in different locations of the Belt. The conclusions are: (1) From 2010 to 2020, 52 cities in the Belt experienced a net loss of population, of which 26 cities continued the negative population growth trend since 2000. (2) There have been systematic differences between shrinking cities and non-shrinking ones in the Belt in terms of population age structure, education structure, industrial structure, public services and others, which means a development differentiation between shrinking cities and non-shrinking ones, a new type of regional disparity besides East-Middle-West and urban-rural areas. (3) The relative location with the central city affects the city size nonlinearly: the cities with the shortest commuting time from the central city less than 50 minutes could likely to obtain positive effect of population growth brought by agglomeration, while cities with the shortest commuting time from the central city between 50 and 450 minutes tend to experience urban shrinkage. Therefore, to promote the overall sustainable development of the Belt, we should optimize the urban system, strengthen the construction of the multimodal transportation network, and reasonably guide the shrinking cities to “slim down and keep healthy”.