Cisplatin resistance remains a significant obstacle for improving the clinical outcome of ovarian cancer patients. Recent studies have demonstrated that cisplatin is an important inducer of intracellullar reactive oxygen species (ROS), triggering cancer cell death. Sirtuin 2 (SIRT2), a member of class III NAD+ dependent histone deacetylases (HDACs), has been reported to be involved in regulating cancer hallmarks including drug response. In this study, we aimed to identify the role of SIRT2 in oxidative stress and cisplatin response in cancer. Two ovarian cancer cell lines featuring different sensitivities to cisplatin were used in this study. We found different expression patterns of SIRT2 in cisplatin-sensitive (A2780/S) and cisplatin-resistant (A2780/CP) cancer cells with cisplatin treatment, where SIRT2 expression was augmented only in A2780/S cells. Furthermore, cisplatin-induced ROS generation was responsible for the upregulation of SIRT2 in A2780/S cells, whereas overexpression of SIRT2 significantly enhanced the sensitivity of cisplatin-resistant counterpart cells to cisplatin. Our study proposes that targeting SIRT2 may provide new strategies to potentiate platinum-based chemotherapy in ovarian cancer patients.