Temozolomide (TMZ) is used for the treatment of high-grade gliomas. Acquired chemoresistance is a serious limitation to the therapy with more than 90% of recurrent gliomas showing little response to a second line of chemotherapy. Therefore, it is necessary to explore an alternative strategy to enhance the sensitivity of glioblastoma (GBM) to TMZ in neuro-oncology. Celecoxib is well known and widely used in anti-inflammatory and analgesic. Cyclooxygenase-2 (COX-2) expression has been linked to the prognosis, angiogenesis, and radiation sensitivity of many malignancies such as primitive neuroectodermal tumor and advanced melanoma. The objective of this study was to explore the chemotherapy-sensitizing effect of celecoxib on TMZ in GBM cells and its potential mechanisms. From the study, we found that the combination therapy (TMZ 250uM+celecoxib 30uM) showed excellent inhibitory effect to the GBM, the LN229 and LN18, which were the TMZ resistant GBM cell lines. Our data suggest that the combination therapy may inhibits cell proliferation, increases apoptosis, and increases the autophagy on LN229 and LN18. The potential molecular mechanisms were related to mitochondrial metabolism and respiratory chain inhibition.