The study evaluates the protective effect of mangiferin on osteosarcoma cell proliferation and metastasis. Saos-2 and U2OS cells were treated with mangiferin (25, 50, 75 and 100 µM) for 72 h. Mangiferin reduced the cell viability, invasion, and cell adhesion and migration rate. Matrix metalloproteinases-2/9 (MMP-2/9) mRNA expression was reduced significantly, while the levels of tissue inhibitors of metalloproteinases-1/2 (TIMP-1/2) were elevated in Saos-2 and U2OS cells. Mangiferin treatment significantly reduced parathyroid hormone receptor 1 (PTHR1) mRNA and protein expression by more than 0.5-fold in both osteosarcoma cells. In addition, the immunofluorescent analysis also showed decreased PTHR1 expression following treatment with mangiferin. In summary, we have demonstrated that treatment with mangiferin reduces cell viability, proliferation, invasion, adhesion and migration, and induces apoptosis of osteosarcoma cells. Therefore, treatment with mangiferin can be effective agent in inhibiting growth and inducing apoptosis in osteosarcoma cells. Our experimental results provide evidence for the therapeutic effect of mangiferin in osteosarcoma cells.