Background <p>The objective of this study was to evaluate the efficacy and safety of esketamine hydrochloride injection (HR020602) in combination with propofol for the induction and maintenance of general anesthesia in children, providing additional support for the use of esketamine in pediatric patients.</p> Methods <p>This phase 2 study (NCT04867343) was conducted in two stages. Stage 1 involved the evaluation of the optimal dosing, and stage 2 was a multicenter, randomized, double-blind, positive control study to evaluate the efficacy and safety of HR020602, on the basis of the dose recommended in stage 1. The primary endpoint was the success rate of anesthesia induction in stage 2.</p> Results <p>In total, 70 children were enrolled (20 children in stage 1 and 50 children in stage 2). The recommended dose was 1.0&#xa0;mg/kg in stage 1. In stage 2, 50 children were randomized (1:1) to the HR020602 group (<i>n</i> = 24) or the fentanyl group (<i>n</i> = 26). Demographics and baseline characteristics were balanced between groups. In stage 2, the primary endpoint, the induction success rate, was 100.0% in both the HR020602 group and the fentanyl group, whereas the maintenance success rate was lower in the HR020602 group (62.5% vs. 92.3%). In stage 2, treatment-related adverse events (TRAEs) occurred in 91.7% of the children in the HR020602 group and 61.5% in the fentanyl group. No serious TRAEs or deaths were reported.</p> Conclusion <p>Compared with fentanyl-based anesthesia, HR020602 at a dosage of 1.0&#xa0;mg/kg, when coadministered with propofol, achieved reliable induction but was associated with a lower maintenance success rate. Further studies on dose optimization and alternative strategies are warranted.</p> Trial registration <p>The study was registered at ClinicalTrials.gov (NCT04867343) on April 30, 2021.</p>