Cultivated land pressure represents a direct reflection of grain security. Existing relevant studies rarely approached the spatiotemporal pattern of cultivated land pressure or the spatial heterogeneity of its influencing factors from the level of economic zones. Taking the Huaihai Economic Zone (HEZ), China for case analysis, this study investigated the spatiotemporal pattern of cultivated land pressure in diverse periods from 2000 to 2018 based on a modified cultivated land pressure index and spatial correlation models. On this basis, it explored the influencing factors of the spatial differentiation of cultivated land pressure in the late stage of the study using geographical detector as well as multi-scale geographically weighted regression model. The results indicated that: 1) in the study period, the global cultivated land pressure index of the study area decreased gradually, but cultivated land pressure increased locally in a significant way, especially in the central and southern Shandong Province; 2) the spatial pattern of cultivated land pressure manifested global clustering features. Hot and secondary-hot spots presented a narrowing and clustering trend, whereas cold and secondary-cold spots manifested a spreading and clustering trend; 3) average slope, the proportion of non-grain crops, population urbanization rate, and multiple cropping index have significant effects on the spatial differentiation of cultivated land pressure. The former three factors were positively correlated with cultivated land pressure, and the last factor was negatively correlated with cultivated land pressure; and 4) the amount of cultivated land has increased in the central and southern Shandong Province through land consolidation which, nonetheless, failed to improve the grain production. In regards to major grain producing areas similar to the HEZ in China, the authors suggest that great importance should be given to the balance of the quality and quantity of cultivated land, the optimization of agricultural production factors and the rational control of non-grain crops, thus providing a powerful guarantee for grain security in China.