<p>Rapid urbanization in China has led to spatial antagonism between urban development and farmland protection and ecological security maintenance. Multi-objective spatial collaborative optimization is a powerful method for achieving sustainable regional development. Previous studies on multi-objective spatial optimization do not involve spatial corrections to simulation results based on the natural endowment of space resources. This study proposes an Ecological Security–Food Security–Urban Sustainable Development (ES–FS–USD) spatial optimization framework. This framework combines the non-dominated sorting genetic algorithm II (NSGA-II) and patch-generating land use simulation (PLUS) model with an ecological protection importance evaluation, comprehensive agricultural productivity evaluation, and urban sustainable development potential assessment and optimizes the territorial space in the Yangtze River Delta (YRD) region in 2035. The proposed sustainable development (SD) scenario can effectively reduce the destruction of landscape patterns of various land-use types while considering both ecological and economic benefits. The simulation results were further revised by evaluating the land-use suitability of the YRD region. According to the revised spatial pattern for the YRD in 2035, the farmland area accounts for 43.59% of the total YRD, which is 5.35% less than that in 2010. Forest, grassland, and water area account for 40.46% of the total YRD—an increase of 1.42% compared with the case in 2010. Construction land accounts for 14.72% of the total YRD–an increase of 2.77% compared with the case in 2010. The ES–FS–USD spatial optimization framework ensures that spatial optimization outcomes are aligned with the natural endowments of land resources, thereby promoting the sustainable use of land resources, improving the ability of spatial management, and providing valuable insights for decision makers.</p>