Background: Any nausea, retching, or vomiting that happens in the post-anesthesia care unit (PACU) or within 24 hours after surgery is referred to as postoperative nausea and vomiting (PONV). The present study was conducted to compare Ondansetron and Palonosetron for prevention of nausea and vomiting following upper abdominal surgeries under general anaesthesia. Materials & Methods: 50 patients between 18 to 65 years of age scheduled for abdominal surgeries under general anaesthesia of both genders were divided into 2 groups of 25 each. Group I received ondansetron 2 mL (4 mg), and group II received 0.075 mg of palonosetron. Duration of anaesthesia, duration of surgery, type of surgery, incidence of nausea and retching etc. was noted. Results: Group I had 12 male and 13 females and group II had 11 males and 14 females. In group I and group II, duration of anaesthesia was 120.1 minutes and 132.1 minutes, duration of surgery was 124.2 minutes and 131.5 minutes. Open surgery was performed in 15 and 14 and laparoscopic surgery in 10and 11 patients. Nausea was seen in 17 and 3 and retching in 14 and 2 patients respectively. The difference was significant (P< 0.05). Conclusion: When it comes to preventing PONV, palonosetron at a dose of 0.075 mg is safe, has fewer side effects, and works better than ondansetron 4 mg.