[Objective] The temporal and spatial evolution characteristics of cropland area and grain prodution was determined in Guangdong Province, in order to provide scientific references for the formulation and implementation of policies regarding cropland protection and food security in the region. [Methods] The methods of change intensity index, center of gravity migration trajectory, and sensitivity analysis model of cropland and grain yield were used to determine the spatial and temporal change characteristics of cropland area and grain yield, and the sensitivity degree of grain yield to cropland area changes at the county scale in Guangdong Province from 2000 to 2020. [Results] ① 88.71% of the counties in Guangdong Province experienced a decrease in cropland area from 2000 to 2020. The counties with decreasing trends in cropland area developed from a concentrated distribution in the Pearl River delta region to a contiguous distribution throughout the entire province. ② 78.23% of the counties had a decrease in grain yield, and counties with significant decreases in grain production were mainly concentrated in the Pearl River delta region. ③ The centers of gravity of cropland area and grain yield both showed movement trends of “southward and westward”. The contribution of cropland area and grain yield in Western Guangdong Province played increasingly important roles in Guangdong Province. ④ The number of counties where grain yield was sensitive to changes in cropland area gradually increased over time, and the sensitive counties were increasingly concentrated in the Pearl River delta region and Eastern and Northern Guangdong Province. [Conclusion] Cropland area and grain yield in Guangdong Province had been decreasing over time, and the regions where grain yield were sensitive to changes in cropland area had been continuously expanding. These results suggest that Guangdong Province should focus on the temporal and spatial changes of cropland area and grain production for policy formulation. Based on changes in grain production, more attention should be paid to regions with higher grain yields. However, classified measures should be implemented to protect cropland, monitor grain production, and increase enthusiasm for grain cultivation.