Esketamine, a potent N-methyl-D-aspartate (NMDA) receptor antagonist with a higher affinity than worldwide used racemic ketamine, has emerged as an important analgesic agent in perioperative pain management. Especially when the use of traditional analgesics is challenging, such as in care of pediatric patients and conscious analgesia and sedation, esketamine is of great value. This chapter reviews the pharmacological profile of esketamine, focusing on its efficacy to provide improved pain relief; the opportunity of administration via diverse routes including intravenous, intranasal, and intrathecal application; and its potential to reduce opioid consumption. Esketamine has little impact on respiratory function, which makes it a preferable option in perioperative pain therapy, enhancing patient comfort without prolonging hospital stay. It is helpful for reducing the incidence of opioid-induced adverse effects and may alleviate chronic pain exacerbated by opioid dependence and hyperalgesia. However, despite all benefits, esketamine’s clinical use must be carefully managed due to possible adverse psychoactive effects. The chapter also highlights the importance of continued study of esketamine in large-scale, multicenter trials to elucidate regimen with best possible analgesic efficacy and safety. This may significantly improve patient outcomes.