Abstract: Objective To compare the effects of different drug combinations on postoperative nausea and vomiting (PONV) in patients undergoing laparoscopic myomectomy under general anesthesia, and to explore the potential mechanisms. Methods A total of 160 female patients who underwent laparoscopic myomectomy at Suzhou Hospital Affiliated to Nanjing Medical University from August 2023 to February 2024 were randomly divided into four groups (n=40): sevoflurane group (Group A), sevoflurane + dexamethasone group (Group B), propofol + dexamethasone group (Group C), and propofol group (Group D). The visual analog scale (VAS) scores were recorded at 10 minutes after extubation and at 6, 12, and 24 hours after surgery, along with the occurrence of PONV at different time points and the use of rescue medication. The serum serotonin (5-HT) levels at baseline (T0) and at the end of the surgery (T1) were measured by ELISA. Results The VAS scores and the occurrence of PONV at 10 minutes post-extubation and at 6, 12, and 24 hours post-surgery were compared among the groups. The difference in PONV incidence from lominutes post-extubation to 6 hours post-surgery was statistically significant (P=0.016). Pairwise comparisons showed a significant difference between Group A and Group C (P=0.011). The use of metoclopramide 6 hours after surgery was also significantly different among the groups (P=0.048), with only Group A and Group C showing a significant difference (P=0.042). At T1, the serum 5-HT level in Group A was significantly higher than in Groups C (P=0.027) and D (P=0.040), with statistically significant differences. Conclusions In laparoscopic myomectomy, the incidence of PONV from lominutes post-extubation to 6 hours post-surgery is significantly lower in patients receiving propofol combined with dexamethasone compared to those undergoing sevoflurane anesthesia. Additionally, the use of metoclopramide is reduced. This may be related to the combined effect of propofol and dexamethasone in lowering serum serotonin (5-HT) levels.