Objective <p>Post-stroke depression (PSD), a common stroke complication, negatively impacts physical function, cognition, and quality of life. Edaravone dexborneol (ED), a combination agent, helps alleviate ischemia-induced damage to neuro-motor and cognitive functions. This study aims to evaluate the neuroprotective effects of ED in a rat model of PSD.</p> Methods <p>The PSD model was established via filament inserting through the internal carotid artery and chronic unpredictable mild stress stimulation. After the model was established, ED treatment was given for 14&#xa0;days (<i>i.p.</i> at a dose of 3mg/kg). Subsequently, the therapeutic effects of ED on behavioral parameters and inflammatory biomarkers in the PSD rats were analyzed.</p> Results <p>ED has a tendency to increase the percentage of sucrose preference in PSD rats. ED could significantly shorten the forced swimming time of PSD rats (<i>P</i> &lt; 0.05). ED significantly increased the level of 5-hydroxytryptamine in the brain tissue of PSD rats (<i>P</i> &lt; 0.05) and reduced the expression of inflammatory markers interleukin-6 and tumor necrosis factor-α (<i>P</i> &lt; 0.05).</p> Conclusion <p>ED demonstrates potential therapeutic efficacy in mitigating depressive-like behaviors in a PSD rat model, reducing neuroinflammation, minimizing brain tissue damage, and conferring neuroprotective benefits.</p>