Abstract： Objective:To study the clinical efficacy and mechanism of action of hyperbaric oxygen combined with escitalopram in the treatment of post-stroke depression.Methods:A total of 90 patients with post-stroke depression admitted to Qingdao Mental Health Center and Qingdao Municipal Hospital from July 2021 to April 2023 were selected as the subject. They were divided into observation group and control group according to the random number table method，with 45 cases in each group. The control group took escitalopram orally，and the observation group was additionally given hyperbaric oxygen therapy on the basis of the treatment of the control group. The neurological function and clinical efficacy of two groups were evaluated by the National Institutes of Health stroke scale（NIHSS）；the cognitive function of two groups was evaluated by the mini-mental state examination（MMSE）Scale；patients’ ability to perform daily activities of life was evaluated by Barthel index（BI）score；the depression status of patients was scored by the Montgomery-Asberg depression rating scale（MADRS）. Before and after treatment，fasting venous blood was collected in the morning，and the levels of serum interleukin（IL）-1，IL-6，IL-8，high-sensitivity C-reactive protein（hsCRP），ciliary neurotrophic factor（CNTF），and brain-derived neurotrophic factor（BDNF）were measured using enzyme-linked immunosorbent assay.Results:The total effective rate of the observation group（91.11%）was higher than that of the control group（71.11%），with a statistically significant difference（ χ2=5.874， P<0.05）. After treatment，the NIHSS and MADRS scores of the observation group were significantly lower than those of the control group，while the MMSE and BI scores were significantly higher than those of the control group（all P<0.001）. Compared with those before treatment，the serum levels of IL-1，IL-6，IL-8，and hsCRP in both groups were significantly reduced after treatment，and the levels of the observation group were significantly lower than those of the control group after treatment（all P<0.001）. Compared with those before treatment，the serum levels of CNTF and BDNF in both groups significantly increased after treatment，and the levels of the observation group was significantly higher than those of the control group after treatment（both P<0.05）. Conclusion:The clinical efficacy of hyperbaric oxygen combined with escitalopram in the treatment of post-stroke depression is good，and its main mechanism of action may be related to improving brain tissue oxygen supply，reducing inflammatory response，and promoting neural function repair.