Abstract: Spatial evolution of the grain production can greatly contribute to the optimization and allocation of the resource elements in the different agricultural zones. Its key influencing factors can also be explored to adjust the spatial layout of grain production. This study aims to divide the distinct stages of the spatial evolution according to the evolutionary context of grain production. The change rate of the grain crops acreage was employed to characterize the speed and direction of the spatial evolution. The “internal-external” conversion features of grain production spaces were then examined to integrate the spatial hotspot detection. A systematic investigation was also made on the spatial evolution and regional differentiation of grain production over the different phases. Finally, a multi-scale geographically weighted regression (MGWR) model was utilized to synthesize the multidimensional driving factors. The socioeconomic and natural environmental elements were also considered to reveal the primary influences on the spatial evolution of the grain production. Furthermore, the driving mechanisms were determined to underlie the regional differentiation of the spatial evolution during grain production. The results showed that: 1) An increasing trend was found in the yield per unit area and acreage of three major grain crops in the three major grain-producing areas from 2000 to 2019. Among them, the main producing areas shared the highest yield per unit area. While the production-marketing balance areas exhibited the largest increase of nearly 40%. Rice was maintained on the largest proportion of the planting areas, and predominantly distributed in the southern regions. Wheat, maize, and maize-wheat planting areas were concentrated in the northern regions. Specifically, the maize planting areas showed the maximum increase (68.16%). While the wheat and maize-wheat planting areas experienced a long-term reduction and expansion, respectively. 2) The internal spatial conversion was dominated by the shift from the wheat to the maize-wheat planting in the Huang-Huai-Hai Plain. The main feature of the external conversion was the spatial expansion of the grain production space. Particularly, the large-scale croplands, forests, and grasslands were converted into the grain planting land in the eastern main grain-producing and the southern production-marketing balance regions. There was a persistently low conversion degree in the western grain production-marketing balance areas. While a high level of the conversion degree was observed in the eastern main grain-producing and the southern production-marketing balance areas. 3) Per farmer non-agricultural income, the proportion of the non-agricultural industries, land urbanization rate, agricultural machinery power per labor force, slope, and annual average temperature were identified as dominant factors of spatial differentiation in grain production conversion. Agricultural producer prices, rural non-agricultural labor force, soil erosion intensity, and annual average sunshine duration were recognized as the significant factors. 4) The regional differentiation was primarily governed by the decision-making and spatial protection, industrial and labor force non-agricultural transition, as well as the composite constraints from topography, climate, and ecological environment. The socio-economic factors interacted with the natural conditions that were subjected to direct constraints and indirect coercion. Ultimately, there was a complex geographic pattern of the spatial evolution. As such, the regional differentiation was also pronounced in the spatial evolution of the grain production. Therefore, the future strategies should optimize the resource allocation and spatial layout using technological innovation, model improvements, and differentiated adjustments. The finding can also provide a scientific basis for food security and differentiated formulation, in order to promote high-quality grain production and sustainable agriculture.