Background and Aim: Postoperative nausea and vomiting (PONV) are common complications following laparoscopic surgeries. Effective management of these symptoms is essential for improving patient recovery and satisfaction. This study aims to compare the efficacy, duration of action, adverse effects, and patient satisfaction of palonosetron and ondansetron in preventing and managing PONV. Material and Methods: This prospective, randomized study was conducted at a tertiary care center in Gujarat from July 2023 to May 2024. Patients undergoing laparoscopic surgeries were randomly assigned to receive either palonosetron (Group P) or ondansetron (Group O) preoperatively. The incidence of nausea and vomiting was assessed at multiple time intervals (0-2, 2-6, 6-24, 24-72, and 0-72 hours). Adverse effects and patient satisfaction were also evaluated. Results: Palonosetron demonstrated superior efficacy in reducing postoperative nausea compared to ondansetron, particularly at the 6-24 hours and 24-72 hours intervals. Ondansetron was more effective in controlling nausea during the first 0-6 hours post-surgery. However, no significant difference was observed between the two groups during the 0-72 hours period. Both drugs were well-tolerated, with no significant adverse effects. Conclusion: Palonosetron offers better control of nausea over a longer postoperative period compared to ondansetron. While ondansetron may be effective in the early postoperative hours, palonosetron’s prolonged action makes it a preferred choice for patients at elevated risk of PONV.