Aims and Objectives: The aim of the study was to compare the anti-emetic efficacy, duration of action, and side effects of Palonosetron, Ondansetron, and Granisetron for anti-emetic prophylaxis of post-operative nausea and vomiting. Methodology: We conducted a prospective, randomized, double blind study on patients undergoing laparoscopic abdominal surgeries. The total 120 patients were divided into three groups of 40 patients. Patients of group A were given injection palonosetron (0.075 mg), group B were given injection ondansetron (4 mg), and group C were given injection granisetron (1 mg), intravenously along with premedication, fifteen minutes prior to induction of general anaesthesia. We analyzed the anti-emetic efficacy, duration of action, and side effects of palonosetron, ondansetron, and granisetron. Results: Total incidence of nausea and vomiting was maximum in ondansetron group with total of 74 compared to 36 in granisetron and 12 in palonosetron group, considering overalapping data in all time intervals and this difference was found to be statistically major. In ondansetron group 18 patients had complete response, while complete response was higher in granisetron group (24) and highest with 28 patients in palonosetron group and this difference was statistically substantial. (p < 0.05). Headache and sedation was found in ondansetron group in 2 and 4 patients respectively while only 1 patient had headache in palonosetron group, 7 patients complained of headache in granisetron group. Conclusion: We conclude that palonosetron is more effective in comparison to granisetron and ondansetron in the prevention of PONV in patients undergoing elective abdominal laproscopic surgeries.