Background: Depression has been shown to share an extremely high comorbidity with heart failure (HF). Ginkgo biloba extract (GBE) is a widely used traditional Chinese medicine in cardiac disease. However, its potential therapeutic effect on depressive symptoms following HF largely remains unknown. In this article, we aimed to investigate its effects in reducing depressive behaviors of a HF mouse model. Moreover, we also discussed whether its effects are associated with changes in neural inflammation and 5-hydroxytryptamine (5-HT) signaling. Methods: Mice were randomly divided into three groups: sham, HF+saline and HF+GBE (150 mg/kg/d) (n=10 per group). Systolic heart failure was induced by ligating the left anterior descending coronary artery. Cardiac functions together with depressive-like behaviors were measured after 4 weeks' treatment. Levels of brain natriuretic peptide (BNP), 5-HT, 5-HT receptor 2A (5-HT2AR), tumor necrosis factor-alpha (TNF-alpha), interleukin- 1 beta (IL-1 beta), vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 (HIF-1), (cleaved) caspase-3, Box and Bcl-2 were analyzed by Western blot, Elisa and immunohistochemistry at the end of the experiments. Results: GBE benefited antidepressant-like behaviors and improved cardiac functions in mice with heart failure. Levels of TNF-alpha, IL-1 beta and 5-HT were reduced in the hippocampus after the administration of GBE. Further experiments revealed that GBE also blocked the release of serotonin in the peripheral blood and triggered HIF-1 induced anti-apoptotic pathways. Conclusion: GBE has potential therapeutic effects in relieving depressive status of patients with HF.