Abstract:Opioids will cause adverse effects such as postoperative gastrointestinal reactions，respiratory depression， hyperalgesia, and addictive potential. Recent studies have advocated for reducing or eliminating opioid use to improve postoperative recovery quality of patients. Esketamine and dexmedetomidine have gained widespread clinical application due to their analgesic, anti-inflammatory, and psychomodulatory properties. This article systematically reviews the clinical advancements in the application of esketamine and dexmedetomidine in perioperative opioid-free anesthesia, evaluating their impact on postoperative recovery outcomes. The combination of these two drugs can reduce postoperative pain，nausea and vomiting, and improve patient satisfaction. The combination demonstrates the safety and efficacy as opioid alternatives in perioperative management.