Objective To explore the effect of continuous infusion of low-dose esketamine on pain in patients with extensive burns. Methods A total of 82 patients who underwent debridement and skin grafting of burn wounds under general anesthesia from January 2023 to February 2024 were selected as the research subjects. The patients were randomly divided into two groups: the observation group received continuous infusion of 5 μg/kg/min esketamine before incision (diluted to 20 mL), while the control group received continuous infusion of the same volume of normal saline. The types of anesthetic induction and maintenance drugs were the same for all patients, and the drugs were used in accordance with the instructions. The heart rate (HR) and mean arterial pressure (MAP) were recorded at the time of entering the operating room (T0), immediately after the infusion of normal saline/esketamine (T1), during incision (T2), and when leaving the operating room (T3). Venous blood was drawn at the time of incision, 10 minutes after incision, and 30 minutes after extubation to measure the levels of stress indicators. Visual analogue scale (VAS) for pain was recorded at 30 minutes after extubation and at 6 h, 12 h, and 24 h after surgery. The sedation-agitation scale (SAS) for sedation and agitation, nausea and vomiting, respiratory depression and other complications were recorded at 30 minutes after extubation and at 6 h, 12 h, and 24 h after surgery. Before surgery, 1 day after surgery, and 3 days after surgery, the Pittsburgh sleep quality index (PSQI) and the Chinese version of the burn-specific pain anxiety scale (C-BSPAS) were scored. Results There was no statistically significant difference in HR and MAP between the two groups at T0-T1 (P＞0.05); while at T2 and T3, the HR and MAP of the observation group were lower than those of the control group (P ＜0.05). Before incision, there was no statistically significant difference in serum Glu, NE, Cor, and SOD levels between the two groups (P＞0.05), but at 10 minutes after incision and 30 minutes after extubation, the levels of Glu, NE, Cor, and SOD in the observation group were lower than those in the control group (P＜0.05). The VAS score of the observation group was lower at 30 minutes after extubation and at 6 h, 12 h, and 24 h after surgery (P＜0.05). There was no statistically significant difference in VAS scores between the two groups at 24 h after surgery (P＞0.05). Compared with the control group, the SAS score at the awakening period of the observation group was lower (P＜0.05), while the incidence of complications such as coughing, shivering, nausea, and vomiting during the awakening period and after surgery was not statistically significant (P＞0.05). Compared with the control group, the observation group required a longer time for the first analgesic demand and used less rescue analgesic drugs (P＜0.05). At 1 day and 3 days after surgery, the PSQI score and C-BSPAS score of the observation group were lower than those of the control group.Conclusion Continuous infusion of low dose esketamin can effectively improve the comfort of patients with burn pain, and does not increase the incidence of adverse reactions. It is a safe way for burn patients to relieve pain