Abstract: Objective To investigate the effects of dexmedetomidine combined with melatonin on the postoperative sleep disturbance (PSD) in patients with laparoscopic hysterectomy. Methods Based on a 2×2 factorial trail design, 96 patients who were scheduled for laparoscopic hysterectomy were divided into four groups according to the random number table method (n=24): a dexmedetomidine and melatonin group, a dexmedetomidine and placebo group, a melatonin and normal saline group, and a placebo and normal saline group. Each group underwent combined intravenous and inhaled anesthesia and were administered with corresponding drugs. Then, the St. Mary's Hospital Sleep Questionnaire (SMH) and Numerical Rating Scale (NRS) were used to evaluate the sleep quality and pain before surgery (T₀), on the day of surgery (T₁), on the first day after surgery (T₂), and on the second day after surgery (T₃). The Pittsburgh Sleep Quality Index (PSQI) and Identity Consequence Fatigue Scale (ICFS) were used to evaluate the incidence of PSD and fatigue one week after surgery. Furthermore, intraoperative propofol and remifentanil dosage, postoperative analgesia remedy, the length of hospitalization stay after surgery, and postoperative adverse reactions were recorded. Results There was no interaction between dexmedetomidine and melatonin (P=0.746). Compared with normal saline, dexmedetomidine significantly reduced the incidence of PSD (31.1% vs 61.7%, P=0.003). The dexmedetomidine group presented remarkable increases in SMH score and decreases in NRS score, ICFS, analgesia recovery ratio and the incidence of vomiting incidence at each time point, compared with the normal saline group (P<0.05). There were no differences in propofol and remifentanil dosage, the length of hospitalization stay and other adverse reactions between the two groups (P>0.05). Compared with placebo, melatonin did not reduce the incidence of PSD (41.3% vs 52.2%, P=0.296). There were no significant differences in SMH score, NRS, ICFS, the dosage of propofol and remifentanil, analgesia recovery ratio, the length of hospitalization stay and the incidence of adverse reactions between the melatonin and placebo groups (P>0.05). Conclusions For patients with laparoscopic hysterectomy, dexmedetomidine combined with melatonin or placebo can reduce the incidence of PSD, improve postoperative sleep quality, reduce postoperative pain, reduce perioperative fatigue score, and reduce the incidence of nausea.