BACKGROUND: Recently, opioid-sparing (OS) interventions have been proposed to facilitate rapid postoperative recovery for patients. However, the advantages of OS anesthesia strategy in laparoscopic abdominal major surgery are still unknown. METHODS: 157 patients undergoing laparoscopic major abdominal surgery were randomly assigned to two groups: Remi (77, remifentanil) and OS (80, esketamine combined with dexmedetomidine), the drugs were administered at 0.2-0.5 mg/kg/h (remifentanil or esketamine) and 0.2-0.7μg/kg/h (remifentanil or dexmedetomidine) in two syringes, respectively The primary outcome was the numeric rating scale (NRS) pain score on postoperative day (POD)1. The proportion of rescue analgesia within 48 h, extubation time, postoperative quality recover scale (PQRS), Pittsburgh Sleep Quality Index (PSQI) on POD30 were also recorded. RESULTS: In the postanaesthesia care unit (PACU), the NRS pain score and the proportion of rescue analgesia in Remi group was significantly higher than that in OS group (3 [1 to 3] vs 1 [1 to 3], CONCLUSION: In this study, OS anesthesia strategy during laparoscopic major abdominal surgery decreases the NRS pain scores in PACU and reduces the use of rescue analgesia, though it may prolong the extubation time and increase the proportion of dreaminess during hospitalization. TRIAL REGISTRATION NUMBER: ChiCTR2200060130.