The ecological and environmental effects caused by land use change have attracted global attention. Huaihai Economic Zone, as the core of the Huaihe River ecological economic belt, has experienced a reciprocal evolution of land use, ecological security and regional economic development. Based on multi-stage land use data extracted by Google Earth Engine (GEE), the spatio-temporal differentiation characteristics of ecosystem service value (ESV) evolution in Huaihai Economic Zone from 1998 to 2018 were analyzed with the help of ESV assessment and a minimum accumulated resistance model (MCR), and the regional ecological security pattern (ESP) was optimized. The results show that ESV intensity has obvious spatial differentiation, which is higher in northeastern China and lower in southwestern China. The median ESV area accounted for the largest proportion, while the high and low ESV areas accounted for a small proportion. The characteristics of EVS temporal and spatial differentiation show decreasing and increasing grades. From the perspective of development period, the ESV grade changes show a positive trend. In the optimization of the ecological security pattern, 26 important ecological sources, 22 main landscape ecological corridors, and 65 ecological strategic nodes were optimized and identified, and the middle-level ecological security zone accounted for the largest proportion. The main reasons for the changes in the ESV and ESP are closely related to the changes in local natural resources and the changes and adjustments in government protection policies. These research results can provide a reference for inter-provincial territorial space protection and the formulation of a sustainable development strategy.