Background: Quercetin has been reported to modulate cell proliferation and apoptosis. The present study aimed at identifying whether treatment of ionizing radiation (IR) combined with quercetin induces apoptosis in HepG2 cells. Materials and Methods: HepG2 cells were plated at an appropriate density according to each experimental scale and irradiated with 1, 5 and 10 Gy gamma-rays from a ⁶⁰Co source at room temperature. Cell viability, SOD and CAT were assessed by using commercial assay kits. Western blot analyses were done on apoptosis related proteins. The cells were treated with various concentrations of quercetin alone or in combination with IR.  Results: The cell viability was decreased in a concentration-dependent manner 24 h after treatment of quercetin. It was significantly lowered after the combined treatment of quercetin with IR than that of the cells treated with quercetin alone. Moreover, quercetin increased the expression of p53 levels in a dose-dependent manner. Combined treatment of quercetin with IR significantly increased the levels of pro-apoptotic proteins, cleaved caspase-3 and caspase-7, and Bax. Cell cycle analyses indicated a drastic increase in the Sub G1 population after quercetin treatment combined with IR. The activity of caspase-3 increased coincidently with apoptosis. The combined treatment of quercetin with IR decreased catalase and superoxide dismutase activities, as well. Conclusion: Quercetin made the radio-resistant HepG2 cells undergo apoptosis by activating p53. These results suggest that the combined treatment of quercetin with IR may provide an effective therapeutic strategy to improve the radiotherapy efficacy.