Abstract: Urban agglomerations have become the hardest-hit areas of air pollution in China today, seriously damaging the regional ecological environment and human health. However, few existing studies have considered how to optimize the land use structure to maximize the natural purification capacity of the atmospheric environment, thereby reducing the established pollution. In view of this, this study takes the urban agglomeration in the middle reaches of the Yangtze River with rapid urbanization and serious air pollution as the empirical object. From the perspective of land use structure, using the high-precision PM_2.5 data retrieved independently, based on the generalized additive model and spatial regression model, this study reveals the nonlinear impact of land use change on PM_2.5 pollution and its spatial spillover effect from 2005 to 2020. The research results show that: (1) From 2005 to 2020, the construction land in the urban agglomeration in the middle reaches of the Yangtze River increased significantly, while the cultivated land continued to decrease. The PM_2.5 pollution increased before 2011 and then decreased, and there was a significant spatial autocorrelation. (2) The impact of land use change on PM_2.5 pollution is a complex nonlinear relationship, in which the impact of construction land and cultivated land changes on PM_2.5 pollution has a marginal decreasing effect. (3) The impact of land use change on PM_2.5 pollution has significant spatial spillover effects, and except for grasslands, the direct effects of landcover on PM_2.5 pollution are greater than the indirect effects. (4) Forest land and grassland effectively reduced PM_2.5 pollution in the region and its neighborhood, and the direct effect of forest land was much higher than that of grassland. On the contrary, construction land significantly increased the PM_2.5 pollution in the region and its neighborhood. However, the impact mechanism of cultivated land on PM_2.5 pollution is complicated, reducing PM_2.5 pollution within the region, but aggravating the neighboring PM_2.5 pollution. The research results help to provide new ideas for the prevention and control of air pollution in China′s urban agglomerations.