Objective:To investigate the clinical efficacy and possible mechanism of bifidobacterium tetralogy combined with escitalopram oxalate in the treatment of patients with depression and to provide evidence for further clinical research.Methods:A total of 100 patients with depression who received treatment in Taizhou Second People's Hospital from September 2019 to March 2021 were included in this study. They were randomly assigned to receive either escitalopram oxalate and placebo (control group, n = 50) or escitalopram oxalate and bifidobacterium tetralogy (observation group, n = 50). All patients received 9 weeks of treatment. Psychological status pre- and post-treatment was evaluated using the Hamilton Rating Scale for Depression and the Hamilton Rating Scale for Anxiety. Serum cortisol, inflammatory factors interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) levels were detected using the enzyme-linked immunosorbent assay. Results:Physiological status scores in each group were significantly lower after treatment compared with before treatment. Scores of the Hamilton Rating Scale for Depression and the Hamilton Rating Scale for Anxiety scores post-treatment in the observation group were (10.78 ± 2.03) points and (6.37 ± 2.58) points, which were significantly lower than those in the control group [(16.78 ± 2.85) points, (13.23 ± 2.95) points, t = 11.40, 13.38, both P < 0.001]. Serum levels of cortisol, inflammatory factors IL-1β and TNF-α in each group were significantly decreased after treatment compared with before treatment. Serum levels of cortisol, inflammatory factors IL-1β and TNF-α post-treatment in the observation group were (137.34 ± 63.29) μg/L, (14.38 ± 6.08)ng/L, (13.95 ± 6.46) ng/L, which were significantly lower than those in the control group [(181.22 ± 59.27) μg/L, (25.94 ± 6.92) ng/L, (20.44 ± 6.24) ng/L, t = 15.29, 6.16, 9.24, all P < 0.001). Conclusion:Bifidobacterium tetralogy combined with escitalopram oxalate is highly effective on depression. The combined therapy can remarkably reduce depression and anxiety symptoms and greatly decrease serum cortisol, IL-1β, and TNF-α levels.