This paper proposes a cost-benefit framework to address the role of parcel and neighborhood conditions, as well as government policies, and investigates the spatial determinants of urban land expansion in Nanjing, one of the sub-centers of the Yangtze River Delta (YRD). Using spatial regression models, we find the significance of the economy of scale, agglomeration, accessibility, and government policies in Nanjing’s urban growth. In the earlier stage, urban expansion in Nanjing was mainly driven by the development of infrastructure. Since entering the 21st century, the emerging commercial and industrial sub-centers have become the major centers of growth, which has changed Nanjing’s spatial structure from compact monocentric to a polycentric one. We also highlight the importance of government policies that have been strengthened by various national strategies, including the “New-type Urbanization” and “Beautiful China” strategies. Different from cities in the Pearl River Delta, Nanjing has a more significant top-down process in its development, which indicates that the municipal government of Nanjing is playing a more important role in urban growth.