Abstract Background A few studies have reported that administration of lidocaine and dexmedetomidine relieves the incidence of postoperative nausea and vomiting (PONV). We explored whether combined infusion of lidocaine plus dexmedetomidine had lower occurrence of PONV undergoing laparoscopic hysterectomy with general anesthesia. Methods A total of 248 women undergoing elective laparoscopic hysterectomy were allocated into the following four groups: the control group (group C, n = 62) received an equal volume of saline, the lidocaine group (group L, n = 62) received intravenous lidocaine (bolus infusion of 1.5 mg/kg over 10 min, 1.5 mg/kg/h continuous infusion), the dexmedetomidine group (group D, n = 62) received dexmedetomidine administration (bolus infusion of 0.5 µg/kg over 10 min, 0.4 µg/kg/h continuous infusion), and the lidocaine plus dexmedetomidine group (group LD, n = 62) received combination of lidocaine (bolus infusion of 1.5 mg/kg over 10 min, 1.5 mg/kg/h continuous infusion) and dexmedetomidine administration (bolus infusion of 0.5 µg/kg over 10 min, 0.4 µg/kg/h continuous infusion). The primary outcome was the incidence of nausea, vomiting, and PONV during the first 48 h after surgery. The secondary outcomes included the incidence of total 24 h PONV after surgery, intraoperative remifentanil requirement, postoperative pain visual analogue scale (VAS) scores and fentanyl consumption, the incidence of bradycardia, agitation, shivering, and mouth dry during post-anesthesia care unit (PACU) stay period. Results The occurrence of nausea and PONV in group LD (5.0 and 8.3%) at 0–2 h after operation was lower than group C (21.7 and 28.3%) (P