Geniposide (GE), an iridoid glycoside from Gardenia jasminoides J.Ellis, exhibits anti-inflammatory, antioxidant, antidepressant, and neuroprotective properties. The excessive presence of corticosterone (CORT) can lead to neurotoxicity and inflict harm upon nerve cells. This study aimed to examine GE's neuroprotective effects on CORT-induced damage in PC12 cells. Cells were pre-treated with GE for 3 h, then exposed to CORT for 24 h. Cell viability and lactate dehydrogenase (LDH) leakage were measured, apoptosis was assessed via flow cytometry, and immunofluorescence was used to detect MAP2 and PSD95 expression. The detection of glutamate (Glu) receptor, BDNF pathway, synaptic plasticity-related protein, and apoptosis pathway were performed using Western blot. The findings indicated that GE effectively prevented the reduction in cell viability, apoptosis, and LDH release caused by CORT. In PC12 cells, the expression of MAP2 and PSD95 were significantly enhanced by GE. Furthermore, GE reduced NR1, NR2A, NR2B, and Bax levels, increased EAAT2/3, Bcl-2, and proteins linked to BDNF and synaptic plasticity, and inhibited Caspase-3 and Caspase-9. GE shows neuroprotective and anti-apoptotic properties against CORT-induced cellular damage through BDNF pathway activation and Bax/Bcl-2 pathway suppression.