The studies of the spatial layout and impact mechanism of pollution-intensive industries have become one of the research hot spots for regional sustainable development. From the viewpoint of enterprise dynamics, this study used a spatial econometric model and kernel density analysis methods to analyze the spatial layout characteristics of pollution-intensive industries in the urban agglomeration in the middle reaches of the Yangtze River (UAMRYR) in 2010, 2015, and 2020, and to explore the reasons for the formation of the spatial divergence of different sub-industries. The results showed that (1) in the past decade, the pollution-intensive industries in the UAMRYR have spatial shift characteristics, basically presenting a “core-edge” pattern from central cities to peripheral cities, and an “agglomeration-diffusion-agglomeration” spatial trend. (2) Different sub-industries had obvious differences in their agglomeration and diffusion trends. The proliferation trend of the non-metallic mineral products industry and the agricultural and sideline foodstuffs processing industry were obvious, which made environmental management difficult. The manufacture of raw chemical materials and chemical products presented the trend of agglomeration, then diffusion, followed by agglomeration, and transferred to areas outside the urban agglomeration, which reduced the pollution to the environment to a certain extent. The spatial pattern of the electricity, heating power production and supply industry were relatively stable, with little overall change. (3) The spatial layout of pollution-intensive industries was mostly driven by the level of economic development and the degree of industrial agglomeration. Innovation capacity and labor cost promoted the spatial diffusion of industries, and the degree of trade openness intensified the agglomeration of pollution-intensive industries in space. The results of the study provided a more microscopic perspective for understanding the changes in the spatial pattern of pollution-intensive industries and served as a reference for the government to formulate industrial and environmental policies.