Background: Postoperative nausea and vomiting (PONV) are distressing complications for patients undergoing surgeries under general anesthesia. This study compares the efficacy of oral Aprepitant and intravenous Ondansetron in preventing PONV. Methods: A randomized control trial was conducted with 80 patients undergoing elective surgeries under general anesthesia, divided into two groups receiving either oral Aprepitant or intravenous Ondansetron. The primary outcomes measured were the incidence of nausea, vomiting, need for rescue antiemetics, patient satisfaction, and side effects. Results: The Aprepitant group demonstrated significantly lower incidences of nausea (67.5% vs. 42.5%, P=0.019) and a reduced need for rescue antiemetics (22.5% vs. 52.5%, P=0.011) compared to the Ondansetron group. Patient satisfaction was higher in the Aprepitant group. Additionally, the incidence of headache as a side effect was lower in the Aprepitant group (25.0% vs. 55.0%, P=0.006). Conclusion: Oral Aprepitant is more effective than intravenous Ondansetron in managing PONV post-elective surgeries under general anesthesia. Its use is associated with higher patient satisfaction and fewer side effects, suggesting it should be considered a preferred option for PONV prophylaxis in such clinical settings. [ABSTRACT FROM AUTHOR]