Objective: To investigate the effect of the ethnodrug Berchemia lineata on the depression-like behaviors induced by lipopolysaccharide (LPS), and to explore its molecular mechanism based on the FGF2/FGFR1 signaling pathway. Methods: SPF male mice were randomly divided into 5 groups: Model group, Berchemia lineata at low-dose group (2 g/kg), Berchemia lineata at medium-dose group (4 g/kg), Berchemia lineata at high-dose group (8 g/kg) and positive control fluoxetine group (20 mg/kg). Forced swimming test (FST), tail suspension test (TST) and open-field test (OFT) were performed 1 hour after drug administration. Another 60 SPF male mice were randomly divided into 6 groups: Control-vehicle group, LPS-vehicle group, Berchemia lineata at low-dose group (2 g/kg), Berchemia lineata at medium-dose group (4 g/kg), Berchemia lineata at high-dose group (8 g/kg) and positive control fluoxetine group (20 mg/kg). Mice were orally administrated with the drug for continuous 7 days followed by the LPS injection after last administration. Sucrose preference test and FST were used to evaluate the depression-like behaviors. Western blot was used to measure the levels of fibroblast growth factor 2 (FGF2), phosphorylation and total levels of fibroblast growth factor receptor 1 (FGFR1) in mouse hippocampus. Results: Berchemia lineata can shorten the immobility time in both the FST and TST without any alteration in locomotor activity in the OFT, suggesting that Berchemia lineata causes the antidepressant-like effect. In addition, Berchemia lineata can significantly increase sucrose preference and reduce immobility time in response to LPS injection. Moreover, it can significantly increase the levels of FGF2 in the hippocampus of the mouse brain and increase the phosphorylation levels of FGFR1. Conclusion: Berchemia lineata exerts the antidepressant-like effects, which are mediated by the activation of the FGF2/FGFR1 signaling pathway in the hippocampus.