Abstract: Esketamine is the S(+)-enantiomer of ketamine. As a novel anesthetic agent, it exerts its core pharmacological effects mainly through highly selective and potent antagonism of N-methyl-D-aspartate (NMDA) receptors. Compared with conventional ketamine, esketamine has advantages such as a faster onset of action, a shorter elimination half-life, rapid recovery, and a significantly lower incidence of neuropsychiatric adverse reactions. At the same time, it retains the characteristics of strong analgesic efficacy and mild inhibitory effects on respiratory and circulatory function.Therefore, it has attracted considerable attention in the fields of perioperative multimodal analgesia and organ function protection. Perioperative organ protection is a key focus in clinical practice and is of great significance for improving patient prognosis. This article systematically reviews the organ-protective mechanisms of esketamine in inhibiting inflammatory responses, alleviating oxidative stress, and suppressing apoptosis, and extends its protective effects from the traditionally emphasized heart, brain, and lungs to the digestive and immune systems. The article highlights the specific issues that need to be addressed in the translational process from laboratory mechanisms to clinical application, providing clear directions for future research.