The ongoing discord between population growth and available land resources poses significant challenges to the sustainable development of human settlements in Guangdong Province. Multi-scenario simulation of land use oriented to the suitable human settlements is essential for the spatial optimization of land use and improvement of human settlements suitability. Five scenarios were established, each designed to assess different levels of suitability demands. The coupled Markov-FLUS model was employed to simulate land use in Guangdong Province in 2030. The simulation results indicated that the proportions of production, living, and ecological land areas were more coordinated under the comprehensive space optimization scenario. In comparison with the standard business-as-usual scenario, the cropland area exhibited an increase in major grain-producing areas, thereby facilitating the construction of high standard cropland. Concurrently, there has been an increase in ecological land in the central cities of the Pearl River Delta and the surrounding regions. This initiative has been demonstrated to enhance the improvement of the ecological environment and human settlements. In comparison with the living space preference scenario, the newly-added construction land increased in eastern and western regions, which was consistent with the requirements of optimizing urban space in Guangdong province. A comparative analysis reveals that spatial configurations within the comprehensive space optimization scenario exhibit enhanced rationality in comparison to alternative scenarios. The land use strategy employed in this scenario proved to be the optimal solution for the conflict between population and land. The findings of this study have the potential to furnish decision-support resources for the future enhancement of land use and the development of human settlements.