Colon cancer is one of the main lethal human cancers with increasing incidence worldwide. We aimed to evaluate the effects of resveratrol in combination with paclitaxel on apoptosis and its underlying mechanisms in the Caco-2 colon cancer cell line. The consequence of resveratrol and paclitaxel on cell viability was measured using MTT assay. Western blot was used for the measurement g-H2AX protein expression. The expression levels of 8-Hydroxy-20-deoxyguanosine (8-oxo-dG) were measured by enzyme-linked immunosorbent assay (ELISA). DCFH-DA fluorescence dye was used to detect reactive oxygen species formation in the colon cancer cell line. The antioxidant activities of some enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase) were also determined. For evaluation of apoptosis, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was applied. Resveratrol dramatically increases the paclitaxel cytotoxic effects. In addition, Resveratrol substantially increased the expression levels of g-H2AX in Caco-2 cells. Furthermore, upon resveratrol treatment, the levels of ROS were increased and the antioxidant enzymes expression levels were significantly decreased. In addition, resveratrol treatment resulted in the enhancement of paclitaxel-induced apoptosis in Caco-2 cells in comparison with either resveratrol or paclitaxel-treated cells. Co-treatment of resveratrol and paclitaxel resulted in increased cellular cytotoxicity through increasing ROS levels, inducing oxidative DNA damage and decreasing cellular antioxidant defense, hence leading to potent apoptosis induction in cancer cell lines. (c) 2023 SAAB. Published by Elsevier B.V. All rights reserved.