BACKGROUND: Despite the implementation of various postoperative management strategies, the prevalence of postoperative fatigue syndrome (POFS) remains considerable among individuals undergoing laparoscopic radical gastrectomy. While the N-methyl-D-aspartic acid receptor antagonist esketamine has demonstrated efficacy in enhancing sleep quality and alleviating postoperative pain, its impact on POFS remains uncertain. Consequently, the objective of this study is to ascertain whether perioperative administration of esketamine can effectively mitigate the occurrence of POFS in patients undergoing laparoscopic radical gastrectomy. METHODS: A total of 133 patients diagnosed with gastric cancer were randomly assigned to two groups, namely the control group (Group C) (n = 66) and the esketamine group (Group E) (n = 67), using a double-blind method. The Group C received standardized anesthesia, while the Group E received esketamine in addition to the standardized anesthesia. The primary outcome measure assessed was the Christensen fatigue score at 3 days after the surgical procedure, while the secondary outcomes included the disparities in postoperative fatigue, postoperative pain, sleep quality, and adverse reactions between the two groups. RESULTS: In the group receiving esketamine, the fatigue scores of Christensen on the third day after surgery were significantly lower compared to the Group C (estimated difference, -0.70; 95% CI, -1.37 to -0.03; P = 0.040). Additionally, there was a significant decrease in the occurrence of fatigue in the Group E compared to the Group C on the first and third days following surgery (P < 0.05). Also, compared to individuals who had distal gastrectomy, those who had entire gastrectomy demonstrated a higher degree of postoperative tiredness reduction with esketamine. Furthermore, the Group E exhibited reduced postoperative pain and improved sleep in comparison to the Group C. Both groups experienced similar rates of adverse events. CONCLUSIONS: The use of esketamine during the perioperative period can improve POFS after laparoscopic radical gastrectomy, without adverse reactions. TRIAL REGISTRATION: Registered in the Chinese Clinical Trial Registry (ChiCTR2300072167) on 05/06 /2023.