Introduction: Postoperative nausea and vomiting (PONV) are among one the greatest common disorders that anesthesiologists and patients encounter following medical procedures. PONV has been treated with a variety of procedures and drugs. Aim: To determine the effectiveness of preoperative Ondansetron and Dexamethasone in the avoidance of Nausea and Vomit ing after Cholecystectomy. Methodology: The study is a one-year double-blind randomized supervised medical experiment. A total of 228 individuals were placed into 3 categories: one received ondansetron, the second received dexamethasone, and the third received filtered water. Cholecystectomy was performed on all of the individuals. Subsequent to the administration of anesthesia, the participants in the initial group got ondansetron (4 mg IV), the next group obtained dexamethasone (8 mg IV), and the final group obtained filtered water. The frequency of Postoperative nausea and vomiting (PONV) and its intensity over the 24-hour period following the operation were evaluated and contrasted utilizing Belleville__ampersandsignrsquo;s scoring method. A randomized controlled trial. This study was conducted at Ghulam Muhammad Mahar Medical College Sukkur Pakistan from February 2020 to March 2021. Results: In the initial two hours following operation, there occurred no substantial variation in PONV across the 3 groups. The PONV in the ondansetron, as well as dexamethasone categories, were considerably lower than the reference group at 2-8, 8-16, and 16-24 hours following the operation. Conclusion: Following Cholecystectomy procedures, ondansetron, as well as dexamethasone, proved significantly more efficacious than placebo in managing PONV. Dexamethasone was also found to be more efficacious than ondansetron in avoiding PONV.