Background: Despite all of the benefits provided by laparoscopic cholecystectomy, such as rapid recovery and shorter hospital stay for patients, the incidence of postoperative nausea and vomiting (PONV) and postoperative pain (POP) still remains high. Objectives: This study was designed to compare the effects of intraperitoneal (IP) and intravenous (IV) dexamethasone on the reduction of PONV and POP. Methods: This prospective, randomized, double-blind clinical trial was conducted on a study population of 86 adult patients who were scheduled for laparoscopic cholecystectomy with the American Society of Anesthesiologists class I-II. The patients were randomized into three groups, namely IP dexamethasone (n = 29), IV dexamethasone (n = 29), and control (n = 28) groups. The patients were followed for clinical outcomes, including PONV, POP, and consumption of antiemetics, and their hemodynamic status during the first 24 hours after the surgery. Results: In the first 24 hours after the operation, no significant differences were observed in nausea (P = 0.41) and vomiting (P = 0.38) between the IP and IV dexamethasone groups. However, there was a lower severity of nausea in the IP group (P = 0.001). Additionally, the visual analog scale score representing POP was significantly reduced in the IP group (P = 0.02). No significant differences in the hemodynamic status were observed after the operation between all the three groups. Conclusions: The administration of 8 mg IP dexamethasone was associated with significantly reduced pain and severity of nausea, but not PONV, after laparoscopic cholecystectomy.