Background: This study aimed to test the beneficial effect of grape seed extract (GSE) (Vitis vinifera) and Vitamin C in oxidative stress and reperfusion injury induced by cardiopulmonary bypass (CPB) in coronary artery bypass surgery. Patients and Methods: In this randomized trial, 87 patients undergoing elective and isolated coronary bypass surgery included. The patients were randomly assigned into three groups (n = 29 each): (1) Control group with no treatment, (2) GSE group who received the extract 24 h before operation, 100 mg every 6 h, orally, (3) Vitamin C group who received 25 mg/kg Vitamin C through CPB during surgery. Blood samples were taken from coronary sinus at (T1) just before aortic cross clamp; (T2) just before starting controlled aortic root reperfusion; and (T3) 10 min after root reperfusion. Some clinical parameters and biochemical markers were compared among the groups. Results: There were significant differences in tracheal intubation times, sinus rhythm return, and left ventricular function between treatment groups compared with control (P < 0.05). Total antioxidant capacity was higher (P < 0.05) in both grape seed and Vitamin C groups at T2 and T3 times. In reperfusion period, malondialdehyde level was increased in control group; however, it was significantly lower for the grape seed group (P = 0.04). The differences in the mean levels of superoxide dismutase and glutathione peroxidase among the three groups were not significant (P > 0.05 in all cases). Conclusions: In our patients, GSE and Vitamin C had antioxidative effects and reduced deleterious effects of CPB during coronary artery bypass grafting surgery.