Background: Limited data exist regarding the use of the esketamine-propofol combination (esketofol) in pediatric surgery. This study aimed to investigate the effect of esketofol versus propofol alone on the perioperative characteristics of children undergoing minor surgery., Methods: Eighty-four children aged two to six years were randomly assigned to either the propofol group or the esketofol group. Intraoperative outcomes included bispectral index, dosage of anesthetics, and extubation time. Postoperative outcomes comprised oropharyngeal airway usage, time to orientation, time to eye-opening, length of stay in the post-anesthesia care unit, the need for rescue opioids, pain rating using the Face, Legs, Activity, Cry, Consolability (FLACC) Scale, Pediatric Anesthesia Emergence Delirium Score, nausea and vomiting, and psychotomimetic symptoms. The FLACC pain score was the primary outcome, and the remaining parameters were considered secondary outcomes., Results: The FLACC Score (2 [1, 3.3] vs. 4 [3, 5.3], P<0.001) and frequency of rescue opioids (14.3% vs. 33.3%, P=0.040) were significantly lower, while Bispectral Index (BIS) was higher (P<0.001) in the esketofol group compared with the propofol group. Moreover, the time to orientation and length of stay in the post-anesthesia care unit (PACU) were significantly longer in the esketofol group compared with the propofol group (P=0.029 and P=0.025, respectively). The other outcomes were similar between the two groups., Conclusions: Esketofol reduces postoperative pain and the need for rescue opioids, but it extends recovery time in the PACU and increases BIS without affecting other outcomes.