The study intended to explore the therapeutic effect of liquiritin on PSD rats and its role in the pathogenesis of PSD.The stroke model was established via middle cerebral artery occlusion, and the PSD model was created using chronic unpredictable mild stress combined with isolated feeding. The expressions of BDNF, Bax, and Bcl-2 proteins in the hippocampus of rats were detected using Western blot and immunofluorescence staining after 6 weeks of modeling.The weight, sucrose consumption and activity of the PSD rats decreased (P < 0.05) compared with the normal control and stroke groups. On the contrary, the weights of the liquiritin and escitalopram groups increased and their sucrose consumption and activity increased in the open-field test (P < 0.05) compared with the PSD and normal saline (NS) groups.The result of immunofluorescence staining and western-blot showed that BDNF and Bcl-2 increased in the liquiritin group and Bax increased significantly in the stroke and PSD groups (P < 0.05).Liquiritin is capable of inhibiting neuronal apoptosis in the hippocampus of PSD rats to improve depression symptoms. This improvement may be achieved by reducing the expression of Bax and increasing the expressions of Bcl-2 and BDNF in the hippocampus of PSD rats.© 2025 The Authors. Published by Elsevier B.V.