Metformin, an AMPK activator, is a widely used medicine for type II diabetes, which has been considered to exert the anti-inflammatory effects. It has been reported that inflammation plays an important role in the pathogenesis of depression. Lipopolysaccharide (LPS) is often utilized to induce depressive-like behavior in mice with respect to recent studies. However, whether metformin alleviates the symptoms of depressive-like behaviors and its mechanisms remain unexplored. The present study investigates whether metformin alleviates LPS-induced depressive-like behavior in mice and aims to explore the mechanisms. We first treated adult mice with LPS (0.83 mg/kg, intraperitoneal) to induce depressive-like behavior model for 24 hours after treatment with or without metformin. Then, the effects of metformin on depressive-like behaviors were detected by tail suspension test and forced swim test. Moreover, quantitative RT-PCR was used to determine the mRNA expression levels of lipocalin 2 (Lcn-2) and inflammatory molecules including IL-1β, IL-6 and von Willebrand factor (vWF), which are concerned with inflammation and Lcn-2. It was shown that LPS-induced mouse depressive-like behaviors, as indicated by the increased time of immobility in tail suspension test and forced swim test, were reversed by metformin. It was also shown that LPS increased the mRNA expression levels of Lcn-2 and inflammation-related molecules such as IL-1β in the amygdala tissue, which could be alleviated by metformin. Taken together, metformin mitigates LPS-induced depressive-like behavior in mice by regulating the expression level of Lcn-2 and inflammation-related molecules, including IL-1β, IL-6 and vWF.Video abstract: http://links.lww.com/WNR/A568.