Introduction: Post-operative nausea and vomiting (POVN) is a common condition and causes much discomfort to the patient. It is not only unpleasant but also can have serious consequences like that of gastric content aspiration, rupture of esophagus, opening up of wounds, subcutaneous emphysema, or pneumothorax. Aim of the Study: To compare the anti-emetic effects of intravenous granisetron, ondansetron and palonosetron for prophylaxis of post-operative nausea and vomiting after laparoscopic surgeries under general anesthesia. Materials and Methods: This was a prospective, randomized, double-blinded, comparative study. A total of 75 patients were divided randomly into three groups each having 25 subjects. Group-A received ondansetron 8 mg, Group-B received Granisetron 2.5 mg and Group-C received Palonosetron 0.75 ug. Both male and female patients, ASA I–II with age ranging from 18–65 years and who underwent elective laparoscopic surgeries under general anesthesia were selected.The incidence of post-operative; nausea, retching and vomiting were studied. Observations and Results: Age, gender and weight were insignificant in all the 3 Groups. Groups-A/C was found to be statistically significant (p < 0.05) in 24–48 and also 12–24 hours. Retchingwas significantly less in Group-C when compared to other two groups. Incidence of vomiting was significantly less in Group-C when compared to Group-A and B. The p-value between Group–A and C was found to be statistically significant (p < 0.05) in 24–48 hours. Conclusion: Prophylactic therapy with palonosetron is more effective than prophylactic therapy with ondansetron and granisetron for the long-term prevention of PONV after laparoscopic surgery.