The South-to-North Water Diversion Project (SNWDP) is believed to drive the next phase of sustainable productivity growth, meeting growing water demand, so as to address increasing environmental sustainability challenges. The Middle Route of SNWDP is regarded as an extremely large long-distance inter-basin water diversion project, which has benefited Henan, Hebei, Tianjin and Beijing since 2014 with great sustainable changes to the cities, groundwater, ecological environment, industrial structure and social development of the beneficiary areas. Taking the number of industrial enterprises above designated size (IEDS) in the water-receiving areas as the research object, this paper takes the year of policy implementation 2014 as the basic time point, evaluating the change of the number of IEDS in the beneficiary areas of the Middle Route of SNWDP through difference-in-difference model. The results show that: (1) The Middle Route of SNWDP promotes the additional growth of the number of IEDS in the beneficiary areas. (2) When the Middle Route of SNWDP promotes the growth of the number of IEDS in beneficiary areas, there is no regional difference for regions with different development levels. (3) The reasons why the Middle Route of SNWDP contributes to the additional growth of the number of IEDS are composed of promoting mixed ownership reform of enterprises in beneficiary areas, increasing water supply and increasing population. However, the Middle Route of SNWDP has not had a significant impact on the traditional total factor productivity or the components of production factors, technology and capital. From the final outcome, the South-to-North Water Diversion Project has played a facilitating role in the sustainable development of large-scale enterprises in the water-receiving areas.