Implant bone defects are the most common phenomenon in the processes of bone transplantation. Evidences have identified that fibroblast growth factor-21 (FGF-21) encourages osteogenesis for patients with implant bone defects. The purpose of this study was to investigate the role of FGF-21 and its potential mechanism in bone mesenchymal stem cells (BMSCs). RT-PCR, Western blotting, flow cytometry, immunofluorescence and immunohistochemistry assays were performed to analyze the role of FGF-21 and intracellular signaling pathways involved in BMSCs. It was shown that FGF-21 increased viability of BMSCs. Treatment with FGF-21 decreased the apoptosis of BMSCs by decreasing pro-apoptosis protein Caspase-3. Results indicated that FGF-21 (2 mg/kg) treatment up-regulated HGF, PI3K and AKT expression in BMSCs. In addition, the protective effects of FGF-21 on BMSCs were canceled by PI3K/AKT inhibitor in BMSCs. Results found that knockdown of HGF abolished FGF-21-decreased PI3K/AKT signal pathway. Furthermore, results demonstrated that FGF-21 presented beneficial effects for implant bone defects in rat model. In conclusion, these results indicate that FGF-21 can improve implant bone defects through HGF-mediated PI3K/AKT signaling pathway in BMSCs.