Background <p>Nonunion of fractures is a major unsolved problem in clinical treatment and prognosis of orthopedics. Bone marrow mesenchymal stem cell (BMSC) exosomes have been proven to be involved in mediating tissue and bone regeneration in a variety of diseases. However, the role of BMSC exosomes in fracture nonunion is unclear.</p> Methods <p>BMSC exosomes were injected into a rat model of nonunion fracture, and the fracture-healing site was detected by micro-CT and the serum metabolites were analyzed by LC-MS/MS.</p> Results <p>The results showed that the exosomes could be successfully isolated from rat BMSCs cultured in an exosome-free medium. Compared with the model group, the fracture site of the exosome-treated rats were healing obviously. Compared with the PBS group, there were 158 up-regulated differential abundance metabolites (DAMs) and 79 down-regulated DAMs in the BMSC-exo group. The DAMs were enriched in ‘Th1 and Th2 cell differentiation’, ‘ErbB signaling pathway’, ‘PPAR signaling pathway’ and ‘HIF-1 signaling pathway’ that were related to the function of cell proliferation and differentiation. DAMs-PE in HIF-1 signaling pathway were the major metabolite to promote fracture healing.</p> Conclusions <p>Our study reveals the mechanism by which BMSC-exosome improves the fracture healing process through metabolic reprogramming and provides a reference for the treatment of fracture nonunion.</p>