Purpose: Common postoperative complications following surgery, particularly acute appendicitis surgery, include postoperative pain and vomiting, which can cause discomfort and delayed recovery time. Methodology: A randomized double-blind placebo-controlled clinical trial was done with 80 cases of acute appendicitis of American Society of Anesthesiologists (ASA) physical status I or II and aged 18-60 y/o scheduled for appendectomy under general anesthesia. Patients were randomly divided into two equal groups: group A received 4 mg of ondansetron IV (2 ml), and group B received 2 ml of normal slain IV (placebo). Pain according to VAS, nausea and vomiting according to clinical symptoms, shivering and sedation according to Bedside Shivering Assessment Scale (BSAS) and the Ramsay Sedation Scale (RSS) at 2, 6, 12, and 24 hours after surgery were evaluated and compared between groups. Results: There was a significant decline in the severity of pain only at 2 hours after surgery between the ondansetron and control groups (5.3±1.0 vs. 6.0±1.0; P=0.01, not showing a difference between the groups in 6, 12, and 24 hours after appendectomy. Post-operative nausea and vomiting at 2 (5% vs. 25%; P=0.03) and 6 (7.5% vs. 27.5%; P=0.04) hours after appendectomy in the ondansetron group. At different times, the ondansetron and control groups did not differ in terms of pethidine consumption, or sedation. Conclusions: In conclusion, our study found that ondansetron was effective in reducing postoperative vomiting after acute appendicitis surgery. However, it did not show a clinically significant effect on postoperative pain.