Food security is important to guarantee national security and people’s livelihoods, but the increasingly serious problem of non-grain production (NGP) on croplands has exacerbated the risk of food security and directly affected the sustainable development of the national economy and society. This study adopted 130 cities (states) in the Yangtze River Economic Belt as the research units and used ArcGIS10.8, GeoDA1.22, and Origin2022 software and spatial autocorrelation, standard deviational ellipse, and GeoDetector methods to conduct analyses. This study explored the spatial evolution patterns and factors influencing cropland NGP in the Yangtze River Economic Belt. The results show, firstly, that the NGP rate of cropland in the Yangtze River Economic Belt increased from 35.85% in 2006 to 38.62% in 2022. The number of cities (states) with mild and moderate NGP decreased, while the number of cities (states) with severe NGP increased significantly. Secondly, the spatial distribution of the rate of cropland NGP in the Yangtze River Economic Belt had a strong positive correlation, with “high–high agglomeration” tending to be dispersed, “low–low agglomeration” tending to be concentrated, and the overall trajectory of the center of gravity migrating from the northeast to the southwest. Thirdly, the single-factor detection found that the per capita food possession, slope, elevation, and average annual precipitation had strong explanatory power regarding the spatial difference in cropland NGP in the Yangtze River Economic Belt, and the interaction of any two influencing factors showed nonlinear enhancement. The results of this study can help to precisely identify the spatial and temporal evolution characteristics of cropland NGP in the Yangtze River Economic Belt, which is of great significance for supporting the country in controlling the risk of NGP cultivation, promoting the sustainable development of the Yangtze River Economic Belt, and guaranteeing food security.