Objective To investigate the effects of echinacoside ( EA) on mitochondrial injury in rats with depression. Methods Sprague-Dawley rats were divided into five groups of control, EA, model, treatment, and fluoxetine groups. A rat model of depression was constructed with chronic unpredictable mild stress (CUMS). Rats in the treatment group were intraperitoneally injected with EA mg / ( kg·d). The weight of the rats was recorded, and the sugar water preference index was detected to evaluate the behavior of the rats. Hematoxylin and eosin staining was used to detect damage of bRain tissue. Apoptosis of bRain cells was detected by TUNEL assay. The mitochondrial membrane potential was detected by JC-1 method . Serum interleukin (IL)-6, IL-1β, tumor necrosis factor-α, and IL-10 (inflammatory cytokines) levels were detected by ELISA. Expression of phosphorylated mitochondrial dynamic associated protein (p-Drp1) in the cytoplasm was detected by Western blot. The content of superoxide dismutase, malondialdehyde, and lactate dehydrogenase, which are markers of oxidative stress, was detected by Kits. Results There were no significant differences in the detection index in the EA group compared with the control group. The model group showed weight loss compared with the control group (P< 0. 01). Sugar water preference was lower (P<0. 01), serum levels of the pro-inflammatory cytokines IL-6, IL-1β, and tumor necrosis factor-α were higher, and levels of the anti-inflammatory cytokine IL-10 were lower in the EA group than in the control group ( all P< 0. 01). BRain tissue injury was aggravated, p-Drp1 expression was lower ( P< 0. 01), and oxidative stress in bRain tissue was higher in the EA group than in the control group (all P<0. 01). However, the treatment group showed therapeutic effects and the above-mentioned pathological injuries caused by CUMS recovered. Conclusions EA can alleviate mitochondrial injury in rats with CUMS.