Tumor necrosis factor-related apoptosis‑inducing ligand (TRAIL) is under clinical development as a cancer therapeutic as it has been shown to induce apoptosis in numerous types of cancer cells without significant toxicity towards normal cells. However, the majority of osteosarcoma (OS) tumors are resistant to TRAIL. Thus, the development of cancer therapeutics that overcome TRAIL resistance is required. In the present study, celecoxib (CXB), a non-steroidal anti‑inflammatory drug, was administered in combination with TRAIL to induce cell apoptosis and the doses of the two drugs were simultaneously reduced. The effects of this combination treatment were examined in MG-63 human OS cancer cell lines in culture. Assays of proliferation, apoptosis and tumor growth were performed, along with analysis of the proteins involved. The results revealed that CXB sensitized TRAIL-resistant MG-63 OS cells to TRAIL‑induced apoptosis through downregulation of cellular B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein, caspase-8 and caspase-3. Furthermore, combination treatment reduced tumor growth in a nude rat model. In conclusion, the experimental results provided evidence that the combined administration of CXB and TRAIL is potentially a novel treatment method of OS tumors.