Background <p>Post-stroke depression (PSD) is a frequent complication that adversely affects recovery and quality of life after stroke. Identifying modifiable risk factors is essential for its prevention. This study examined whether health literacy assessed during hospitalization is associated with depressive symptoms three months after discharge in　acute stroke patients who were discharged home.</p> Methods <p>A prospective cohort study was conducted with 451 patients admitted to an acute care hospital, of whom 64 met the eligibility criteria and were included in the final analysis. Health literacy was evaluated prior to hospital discharge using the 16-item European Health Literacy Survey Questionnaire (HLS-EU-Q16). Depressive symptoms were assessed three months after discharge with the 15-item Geriatric Depression Scale (GDS-15) administered via mailed questionnaire. Univariate and multivariate linear regression analyses were performed to examine the association between health literacy and post-discharge depressive symptoms.</p> Results <p>In the univariate regression analysis, higher health literacy was significantly associated with fewer depressive symptoms after discharge (B =  − 0.09, β =  − 0.27, 95% CI [− 0.18, − 0.01], <i>p</i> = .026). This inverse association remained significant in the multivariate model after adjustment for potential confounders (B =  − 0.11, β =  − 0.31, 95% CI [− 0.20, − 0.02], <i>p</i> = .021).</p> Conclusions <p>Health literacy assessed during hospitalization was independently associated with depressive symptoms three months after discharge in acute stroke patients who were discharged home. Assessing health literacy prior to discharge and providing inpatient support tailored to patients’ health literacy levels may help reduce the risk of post-stroke depressive symptoms and support psychological recovery after discharge.</p>