Mesenchymal stem cell-mediated bone tissue engineering strategies, including human dental pulp stem cells (hDPSCs), represent an effective therapeutic approach for bone defect repair, particularly in maxillofacial bone defects. Growth differentiation factor 15 (GDF15), a multifunctional cytokine, plays a critical role in bone tissue formation and remodeling. This study aims to investigate the effects of GDF15 on the osteogenic differentiation of hDPSCs and elucidate the underlying molecular mechanisms. Our findings demonstrate that GDF15 expression and secretion are upregulated during the osteogenic differentiation of hDPSCs. Both overexpression and recombinant human GDF15 (rhGDF15) treatment significantly enhanced the osteogenic differentiation of hDPSCs, whereas knockdown produced the opposite effect. experiments demonstrated that hDPSCs treated with rhGDF15 significantly enhanced new bone formation within implants in both nude mouse subcutaneous transplantation and rat calvarial defect models. Proteomic analysis identified significant enrichment of the TGF-β/SMAD signaling pathway. Molecular docking analysis and co-immunoprecipitation demonstrated the direct binding interaction between GDF15 and TGF-βR2. Both Western blotting and immunofluorescence assays confirmed pathway activation. Critically, pharmacological inhibition of this pathway partially reversed the rhGDF15-induced enhancement of osteogenic differentiation in hDPSCs. Collectively, our findings demonstrate that GDF15 promotes osteogenic differentiation of hDPSCs through activation of the TGF-β/SMAD signaling pathway, thereby proposing a novel therapeutic strategy for bone repair and regenerative treatment.