The analgesic benefit of melatonin and vitamin C as primary or adjuvant agents has been reported in various studies; however, their analgesic effects in the treatment of postoperative pain remain unclear. Thus, we aimed to evaluate the effect of single preoperative dose of oral melatonin or vitamin C administration on postoperative analgesia. In this study, we recruited 165 adult patients undergoing elective major abdominal surgery under general anesthesia. Patients were randomly divided into three equal (n = 55) groups. One hour before surgery, patients received orally melatonin (6 mg) in group M. vitamin C (2 g) in group C, or a placebo tablet in group P. Pain, sedation, patient satisfaction, total morphine consumption from a patient-controlled analgesia device, supplemental analgesic requirement, and the incidence of nausea and vomiting were recorded throughout 24 h after surgery. The mean pain score and total morphine consumption were found significantly lower in both M and C groups compared with group P (p < 0.001). There were no significant differences between group M and C with respect to pain scores (p = 0.117) and total morphine consumption (p = 0.090). Patients requested less supplemental analgesic and experienced less nausea and vomiting in groups M and C compared with group P. In conclusion, preoperative oral administration of 6 mg melatonin or 2 g vitamin C led to a reduction in pain scores, total morphine consumption, supplemental analgesic requirement, and the incidence of nausea and vomiting compared with placebo.