Host immune response to bone biomaterials critically regulates osteogenic differentiation. In this research, electrospun membranes composed of poly-l-lactic acid (PLLA) with different configurations and sizes were created, and the molecular mechanisms through which PLLA electrospun membranes facilitate osteogenic differentiation were investigated. First, these findings suggest that the aligned 600 nm group most effectively polarized macrophages toward the M2 phenotype. Then, the conditional medium coculture system of macrophages and bone mesenchymal stem cells (BMSCs) revealed that PLLA electrospun membranes promote osteogenic differentiation of BMSCs by driving M2 macrophage polarization. Finally, integrated multiomics and experimental validation demonstrated that the PLLA electrospun membrane enhances IL10 expression through the reprogramming of macrophages, which subsequently leads to the inhibition of the JAK2-STAT3 pathway. Collectively, the PLLA electrospun membrane promotes osteogenic differentiation of BMSCs through the "M2 macrophage polarization-IL10/JAK2/STAT3 pathway" cascade axis. Our work provides insights into designing osteoimmunomodulatory biomaterials for osteogenic differentiation.