Background The current research compared the effectiveness of dexamethasone with ondansetron in terms of the frequency of postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy. Methodology A comparative cross-sectional study was conducted in the Department of Surgery, Civil Hospital, Karachi, Pakistan, between June 2021 and March 2022. All patients aged between 18 and 70 years who were scheduled for elective laparoscopic cholecystectomy under general anesthesia were included in the study. All women who were on antiemetics or cortisone before surgery pregnant, and had hepatic, or renal malfunction were excluded. Group A included patients who were administered 8 mg of dexamethasone intravenously, and group B included patients who were prescribed 4 mg of ondansetron intravenously. Observation of patients was done for any symptoms such as vomiting, nausea, or the need for any antiemetic medication after the surgery. The number of episodes of vomiting and nausea was recorded in the proforma along with the duration of stay in the hospital. Results A total of 259 patients were examined during the study - 129 (49.8%) in the dexamethasone group (group A) and 130 (50.2%) in the ondansetron group (group B). The mean age of group A was 42.56 ± 11.9 years, with a mean weight of 61.4 ± 8.5 kg. The mean age of group B was 41.19 ± 10.8 years, with a mean weight of 62.56 ± 6.3 kg. Upon assessing the effectiveness of each drug in preventing nausea and vomiting, postoperatively, it was found that both drugs were equally effective in preventing nausea in the majority of the patients (73.85% vs. 65.89%; P = 0.162). However, ondansetron was significantly more effective in preventing vomiting in patients than dexamethasone (91.54% vs. 79.07%; P = 0.004). Conclusions This study concluded that the use of either dexamethasone or ondansetron effectively reduces the incidence of postoperative nausea and vomiting. However, ondansetron was significantly more effective in reducing the incidence of vomiting in patients after laparoscopic cholecystectomy than dexamethasone.