Post-stroke depression (PSD), a common complication after stroke, severely affects the recovery and quality of life of patients with stroke. Owing to its complex mechanisms, PSD treatment remains highly challenging. Hippocampal synaptic plasticity is one of the key factors leading to PSD; however, the precise molecular mechanisms remain unclear. Numerous studies have found that neurotrophic factors, protein kinases, and neurotransmitters influence depressive behavior by modulating hippocampal synaptic plasticity. This review further elaborates on the role of hippocampal synaptic plasticity in PSD by summarizing recent research and analyzing possible molecular mechanisms. Evidence for the correlation between hippocampal mechanisms and PSD helps to better understand the pathological process of PSD and improve its treatment.