BACKGROUND AND PURPOSE Sigma-1 receptor (Sigma-1R), a chaperone protein with the ability to activate brain-derived neurotrophic factor (BDNF) signaling, has been connected with antidepressant action. Our previous study indicated that loganin has antidepressant-like effects. This study aimed to investigate whether loganin exerts antidepressant-like effects via Sigma-1R/BDNF signaling. EXPERIMENTAL APPROACH We established rat model of depression using chronic unpredictable stress (CUS). Sucrose preference test (SPT) and open field test (OFT) were used to evaluate the antidepressant-like effects of loganin. Then, we assessed the changes of BDNF signaling, synaptic plasticity and neurogenesis in hippocampus using western blot and immunohistochemical analysis. To confirm the role of Sigma-1R and BDNF in loganin-induced antidepressant-like effects, BD1047 and ANA-12 were used to block Sigma-1R and BDNF, respectively. KEY RESULTS Loganin improved depressive-like behaviors of rats in the SPT and OFT. Antidepressant-like effects of loganin in the SPT occur at day 6, which was faster than fluoxetine. Mechanismly, loganin effectively restored CUS-induced decrease in BDNF, pERK/1/2, PSD-95 and DCX in the hippocampus. Blockage of BDNF signaling with ANA-12 reversed the antidepressant-like effects of loganin. Moreover, loganin exhibited a binding affinity with Sigma-1R, as indicated by molecular docking. Importantly, BD1047 diminished loganin-induced improvement of rat behaviors as well as activation of hippocampal BDNF signaling. CONCLUSIONS AND IMPLICATIONS In conclusion, loganin exerts antidepressant-like effects by improving synaptic plasticity and neurogenesis in the hippocampus dependent on Sigma-1R/BDNF signaling.