Objective Metformin(Met)is a commonly used hypoglycemic drug in clinical practice. Regulation of energy metabolism is one of the main mechanisms of its pharmacological action. In this study, we investigated the antidepressive effect of metformin on the basis of mitochondrial oxidative respiratory chain-related genes and explored the related mechanism of its antidepressive effect from the perspective of energy metabolism. Methods ICR mice were injected subcutaneously with corticosterone(20 mg/ kg)for 3 weeks to induce a mouse model of depression-like behaviors. One week after injection, metformin ( 200, 100 and 50 mg/ kg) was administered by gavage for 2 weeks. During administration, the preference rate of sucrose was measured. At the end of administration, an open field test was conducted, and the times and duration of mice traveling in the central area and the distance traveled in the peripheral area were recorded. qPCR and Western blot were used to detect the mRNA and protein expression of mitochondrial respiratory chain related genes NADH dehydrogenase ubiquinone (Nduf), mitochondrial ribosomal protein (Mrp), brain-derived neurotrophic factor(BDNF), cAMP response element-binding protein(CREB), and postsynaptic receptor α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor(AMPAR), and N-methyl-d-aspartic acid receptor(NMDAR) in the hippocampus. The effects of metformin(administration for 1 week)on normal mice were also observed. Results Metformin did not affect the weight of normal or model mice. The sucrose preference rate was enhanced after metformin administration in normal and model mice. In the open field test, metformin increased the number of entrances to the central area in normal and model mice, and increased the distance traveled in the peripheral area in model mice. Additionally, metformin upregulated the mRNA expression of most Nduf subtypes(except for Ndufa8 and Ndufa13)and Mrp, the mRNA expression of Creb, Ampar, Nmdar and protein expression of BDNF, CREB, AMPAR, NMDAR in the hippocampus of normal mice, while antagonizing downregulation of Bdnf, Creb mRNA expression and BDNF, CREB protein expression in model mice. Conclusions Metformin improves depression-like behavior induced by corticosterone in mice. Its mechanism is related to regulating the expression of genes and proteins related to the mitochondrial oxidative respiratory chain and neural plasticity in the hippocampus.