Background <p>Postoperative sleep disturbance (PSD) is common after gynecological laparoscopic surgery and is associated with delayed recovery and adverse emotional outcomes. Stellate ganglion block (SGB) and esketamine have each been reported to modulate perioperative stress responses. We hypothesized that adding an esketamine-adjuvanted SGB to a perioperative multimodal sleep (PMS) strategy based on intraoperative esketamine and dexmedetomidine would reduce PSD.</p> Methods <p>In this prospective randomized controlled trial, 220 of 222 screened patients scheduled for elective gynecological laparoscopic surgery were randomized and assigned to either a control group receiving intraoperative esketamine and dexmedetomidine or an intervention group receiving an esketamine-adjuvanted SGB before anesthesia induction in addition to the same intraoperative regimen. The primary outcome was the incidence of PSD on postoperative days 1 and 3. Secondary outcomes included postoperative anxiety and depression, pain intensity, use of rescue medication, and perioperative complications.</p> Results <p>A total of 192 patients were included in the per-protocol (PP) analysis. The incidence of PSD was significantly lower in the intervention group than in the control group on postoperative day 1 (62.9% vs. 83.2%, <i>P</i> = 0.002) and postoperative day 3 (25.8% vs. 42.1%, <i>P</i> = 0.017). The intervention group also exhibited a lower incidence of early postoperative anxiety. In subgroup analyses, the intervention was associated with a significantly lower incidence of PSD in patients with preoperative depressive symptoms. Independent risk factors for PSD included preoperative sleep disturbance, preoperative anxiety, resting pain, abdominal drainage tube placement, and total hysterectomy. No significant differences in adverse events were observed between the two groups.</p> Conclusions <p>In this single-center randomized trial, adding an esketamine-adjuvanted stellate ganglion block to intraoperative esketamine and dexmedetomidine was associated with a lower incidence of postoperative sleep disturbance after gynecological laparoscopic surgery, without an apparent increase in perioperative complications. These findings require confirmation in larger multicenter studies incorporating objective sleep assessments.</p> Trial registration <p>This study was registered in the Chinese Clinical Trial Registry (ChiCTR2300078436) on December 8, 2023.</p>