Since 2000, the Yangtze River Delta region has undergone a period of rapid urbanization in China. A large area of cultivated land has been converted into construction land, which greatly affects food security. The decrease in cultivated land caused by urbanization is also very serious in Jiangsu Province, one of the main grain-producing areas in the Yangtze River Delta region. Based on the remote sensing data of Jiangsu Province in 2000, 2010 and 2020, this paper analyzes the land use changes occurring in 13 regional cities in Jiangsu Province from 2000 to 2020 by using the transfer matrix. Spatial and temporal geographical weighted regression models were used to analyze the differences in the economic, social and policy impacts of land use change across the province. The results show that the cultivated land area is decreasing, and the closer to the urban center, the faster the decrease in cultivated land in Jiangsu Province. Cultivated land was mainly transferred out to construction land, waters and woodlands. The human factors affecting the change in cultivated land area in the province can be divided into a population growth factor, economic development factor, rural development factor and land policy factor. Among them, population growth and economic development had a negative effect on cultivated land protection, while improvements in the agricultural production level and cultivated land protection policy had a positive effect on cultivated land protection. According to the analysis of spatial-temporal heterogeneity of cultivated land area change, the growing urbanization rate had the greatest impact on the cultivated land area in Southern Jiangsu, and the impact of real estate development on cultivated land has been reduced in small cities. The conclusion of this paper has important policy implications for promoting cultivated land protection and ensuring food security.