Objective <p>In patients undergoing laparoscopic hysterectomy, this study compared two anesthetic approaches—esketamine-based opioid-free anesthesia and opioid-based anesthesia—to assess their impact on postoperative recovery quality.</p> Patients and methods <p>This prospective trial randomly assigned 91 patients undergoing laparoscopic hysterectomy to receive either esketamine-based anesthesia (induction and maintenance with esketamine, without perioperative opioids) or conventional opioid-based anesthesia. The primary endpoint was defined as the Quality of Recovery-40(QoR-40) score measured on postoperative day (POD) 1. Secondary measures comprised the QoR-40 score on POD 3, pain scores after surgery, hemodynamic variables, and adverse events.</p> Results <p>On POD1, compared to the opioid group, the esketamine group exhibited a significantly elevated QoR-40 score (<i>p</i> &lt; 0.001), but scores were similar by POD3 (<i>p</i> = 0.333). The esketamine group experienced a lower rate of postoperative nausea and vomiting (PONV) (17.8% vs. 37.0%, <i>p</i> = 0.040), whereas the two groups had comparable pain scores at every time point measured (all <i>p</i> &gt; 0.05).</p> Conclusion <p>Among laparoscopic hysterectomy patients, esketamine-based opioid-free anesthesia was linked to higher POD1 QoR-40 scores and fewer PONV events than opioid-based anesthesia. However, given the modest sample size, these preliminary findings warrant confirmation in larger multicenter trials.</p> Trial registration <p>We prospectively registered the study protocol in the Chinese Clinical Trial Registry. (ChiCTR2300075661) on September 12, 2023.</p>