The efficacy and safety data of sufentanil or hydromorphone usage are limited for children undergone repair of the structural congenital malformation. This study was aimed to compare the safety and efficacy of these drugs given in combination with flurbiprofen axetil as the postoperative analgesia in children. Children undergone the repair of structural congenital malformation in 9 centers were included in this study (n = 910). Patients were randomly grouped as: H1, hydromorphone 0.1 mg/kg; H2, hydromorphone 0.2 mg/kg; and C, sufentanil 1.5 µg/kg. All the patients also received 5 mg/kg diluted flurbiprofen axetil. Drugs were diluted to 100 mL by 0.9% saline and injected through intravenous electronic analgesic pump with background dose of 2 mL/h. Primary endpoint included the Face, Legs, Activity, Cry and Consolability (FLACC) score, while secondary endpoints had the Ramsay sedation score, heart rate (HR), respiration rate (RR), pulse oxygen saturation (SpO2) and side-effects in 48 h of surgery. No significant differences in HR, SpO2 and RR were observed among the groups in the period from post-anesthesia care unit (PACU) discharge to 48 h of discharge. However, the intergroup differences in FLACC score at the time of discharge from the PACU till 36 h later were statistically significant. FLACC score was lower in the H2 group compared to other two groups. Moreover, the adverse reactions were higher in group C compared to the other groups. These results depicted that hydromorphone hydrochloride 0.2 mg/kg and flurbiprofen axetil 5 mg/kg had better efficacy with fewer adverse effects than sufentanil 1.5 µg/kg with flurbiprofen axetil 5 mg/kg in the pediatric population undergone repair of the structural congenital malformation.