Nausea and vomiting are some of the most common complaints of patients after any anesthesia, which is often associated with postoperative pain. The double-blind clinical trial study aimed to compare the prophylactic effect of dexamethasone and dexmedetomidine and their combination in reducing postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy. One hundred sixty-two patients undergoing laparoscopic cholecystectomy were enrolled in the study. In the first group of patients, 25 mg of dexmedetomidine were administered slowly. In comparison, the patients in the second group received dexamethasone (4 ml/2 mg) with 0.1 mg/kg of normal saline solution. The third group received a combination of dexmedetomidine and dexamethasone. Hemodynamic changes were recorded during surgery and after surgery, and the patients were admitted to recovery. Nausea and vomiting scores were recorded 2 and 4 hours after surgery. Blood pressure and heart rate were lower in the dexmedetomidine group at all times (P<0.05). Two hours after surgery, the dexamethasone and dexmedetomidine combination group had less vomiting (P=0.012). The incidence of nausea 2 and 4 hours after surgery was lower in the dexamethasone and dexmedetomidine combination group (P<0.05). Blood pressure and heart rate were lower in the dexmedetomidine group at all times. The dexmedetomidine and dexamethasone combination decreased postoperative nausea and vomiting in patients. Therefore, we recommend using a dexmedetomidine and dexamethasone combination for reducing postoperative nausea and vomiting.