PURPOSE: This study aimed to investigate the effect of small-conductance calcium-activated potassium channels (SK channels) on the dopaminergic (DA) neuron pathways in the ventral tegmental area (VTA) during the pathogenesis of post-stroke depression (PSD) and explore the improvement of PSD by inhibiting the SK channels. PATIENTS AND METHODS: Four groups of Sprague-Dawley rats were randomly divided: Control, PSD, SK channel inhibitor (apamin) and SK channel activator (CyPPA) groups. In both control and CyPPA groups, sham surgery was performed. In the other two groups, middle cerebral arteries were occluded. The behavioral indicators related to depression in different groups were compared. Immunofluorescence was used to measure the activity of DA neurons in the VTA, while qRT-PCR was used to assess the expression of SK channel genes. RESULTS: The results showed that apamin treatment improved behavioral indicators related to depression compared to the PSD group. Furthermore, the qRT-PCR analysis revealed differential expression of the KCNN1 and KCNN3 subgenes of the SK channels in each group. Immunofluorescence analysis revealed an increase in the expression of DA neurons in the VTA of the PSD group, which was subsequently reduced upon apamin intervention. CONCLUSION: This study suggests that SK channel activation following stroke contributes to depression-related behaviors in PSD rats through increased expression of DA neurons in the VTA. And depression-related behavior is improved in PSD rats by inhibiting the SK channels. The results of this study provide a new understanding of PSD pathogenesis and the possibility of developing new strategies to prevent PSD by targeting SK channels.