Osteosarcoma is the most common form of primary malignant bone tumor. Patients who are insensitive to chemotherapy treatment often have a poor prognosis. According to our previous study, recombinant adenovirus (Myc-AS) in combination with caffeine enhances the induction of apoptosis and the chemotherapeutic effects of cisplatin (CDDP) in MG-63 osteosarcoma cells. The present study aimed to investigate the combinational effects of the small interfering RNAs (siRNAs) c-myc and Bmi-1 on the growth and chemosensitivity of MG-63 osteosarcoma cells. The results indicated that the cell growth inhibition rates of MG-63 cells gradually increased with increasing concentrations of CDDP (P<0.05). This observation was consistent in the single and combined siRNA groups. At a concentration of 5.0 µg/ml CDDP, the growth inhibition rates were 53.3±5.2, 42.7±6.3 and 40.9±4.7% in the combined, c-myc and Bmi-1 siRNA groups, respectively. The cell growth inhibition rate in the combined siRNA group was higher than that observed in the two single siRNA groups (P<0.05). The cell apoptotic rate was 37.3±4.9% in the combined siRNA group, which was significantly higher than that observed in the c-myc (24.8±5.6%) and Bmi-1 siRNA groups (22.7±6.1%; P<0.05). These results suggest that the chemosensitivity of MG-63 cells to CDDP may be markedly enhanced in the siRNA combination group. A decrease in cell proliferation and increased cell apoptosis were also observed in the siRNA combination group. The present study may provide novel insights to further elucidate the pathogenesis and drug resistance mechanisms involved in osteosarcoma. It may also improve our understanding of the underlying mechanisms involved in chemotherapeutic sensitivity, and thus aid the development of future therapeutic strategies for the treatment of osteosarcoma.