The expression of Hic-5 was detected in osteosarcoma patients and osteosarcoma cell lines by RT-PCR. Then RFP-sh-Hic-5 was transfected into osteosarcoma cell lines. The effect of Hic-5 on cell viability, proliferation and apoptosis were assessed by MTT, EdU kit and Flow cytometry. The exosomes were isolated from MG-63 cell supernatant by an Exosome Isolation Kit. The exosome-Hic-5 was confirmed by transmission electron microscope, particle size detection and RT-PCR. Next, exosome-Hic-5 treated cells were explored the cell viability, proliferation and apoptosis. Further, Co-IP assay was employed for identifying the relationship between Hic-5 and smad4. TCF/LEF and the protein level of components of wnt/β-catenin signals were detected by TOP luciferase assay and western blot. Hic-5 was upregulated in osteosarcoma tissues and cell. Forced decreased expression Hic-5 inhibited the proliferation of osteosarcoma cell lines, and induced apoptosis of MG-63 and HOS. In vivo, silencing Hic-5 remitted the tumor progression. Further, we isolated the exosomes from MG-63 supernatant, exosomes concluding Hic-5 would regulated the proliferation and apoptosis level of MG-63 and HOS cells. Further, Hic-5 interacted with smad4 and regulated Wnt/β-catenin signal by decreasing TCF/LEF activity. Silencing Hic-5 inhibited the proliferation and induced apoptosis of osteosarcoma cell via inactivating Wnt/β-catenin signal by exosome pathway.