One of the most prevalent issues with anesthesia is postoperative nausea and vomiting (PONV) in patients having laparoscopic cholecystectomy while under general anesthesia. Since Palonosetron is a 5-HT3 receptor antagonist of the second generation, it may be more effective than other 5-HT3 antagonists when used alone to prevent PONV. Aim: comparing the efficacy of palonosetron + dexamethasone in preventing postoperative nausea and vomiting (PONV) in patients having general anesthesia for laparoscopic cholecystectomy compared to palonosetron alone in the first twenty-four hours after surgery. Patients and Methods: Taking place from January to October 2023, this prospective randomized trial was carried out at Badr University Hospital, which is part of Helwan University. Ninety individuals who were about to have laparoscopic cholecystectomy while under general anesthesia were part of the research. Group PD consisted of 45 patients given palonosetron 0.075 mg in addition to 8 mg of dexamethasone, while Group P consisted of 45 patients given palonosetron alone. Within the first six hours (early PONV) and between six and twenty-four hours (late PONV), patients were polled using a questionnaire to assess postoperative nausea and vomiting (PONV) based on the Rhodes index. Results: Late nausea occurred 20% of patients in group P compared to 4.4% in group PD, with statistically significant difference (p < 0.05). The percentage of patients who needed rescue antiemetic throughout the first 6 hours in group P (8.9%) were comparable with those in the group PD (6.7%). The percentage of patients who needed rescue antiemetic throughout the ˃6–24 hours in the group P (11.16%) were higher than those in the group PD (4.4%), with no statistically significant difference (p > 0.05). When comparing the two groups' median Rhodes scores for vomiting frequency, there was a statistically significant difference between the P group and the PD group at 0-6 hours (two against one), but no difference between the two groups at 6-24 hours. At both the 0-6 and 6-24 hour marks, there was a statistically significant difference in the median ratings of vomiting distress between the two groups, with 2 in the P group and 1 in the PD group, respectively. This difference persisted throughout the whole duration of the study. The median scores of the two groups differed significantly in terms of vomiting amount only at ˼6-24 hours (1 in the P group versus 0 in the PD group). At 0-6 hours, there was a statistically significant difference in the median Rhodes scores of retching frequency between the two groups. One patient in the P group and zero in the PD group were involved in this study. Conclusion: Combining palonosetron with dexamethasone was more effective than palonosetron alone in lowering the incidence of postoperative nausea and vomiting (PONV) in patients receiving laparoscopic cholecystectomy within the first 24 hours after surgery.