The rapid economic development and climate change have accelerated the changes in China's food production and have a potential impact on food security. In this paper, the grain sown area from 2001 to 2019 was selected to analyze the spatio-temporal evolution and driving factors of China's grain production through spatial autocorrelation analysis and geographically weighted regression. Our findings were as follows: (1) From the perspective of time characteristics, China's grain production from 2001 to 2019 experienced four stages: rapid decline, rapid growth, steady growth, and slow decline, although with an overall upward trend. (2) From the perspective of spatial characteristics, the overall spatial pattern had a significant positive correlation. The high values were mainly concentrated in Shandong, Anhui and Jilin, and moved to the northeast China as time went on. (3) In terms of influencing factors, the positive impact of agricultural labor force on the grain production gradually decreased, showing a decreasing trend from southwest to northeast. The promotion of agricultural mechanization on the grain production increased year by year, with the spatial distribution characteristics of high in the northeast and low in the southwest. Besides, the coefficient of water resources endowment was negative, showing a spatial distribution pattern of high north and low south.