Stroke is a leading cause of mortality and disability. This study aimed to investigate the temporal and directional relationships between post-stroke depressive symptoms and cognitive impairment using a cross-lagged panel design. Depressive symptoms and cognitive impairment are two common post-stroke complications. However, the precise underlying mechanism remains unclear despite their close relationship. Therefore, elucidating the causal relationship between these two issues is of great clinical significance for improving the poor prognosis of stroke.This study employed a hospital-based multicenter prospective cohort design. A total of 610 patients with ischemic stroke were eligible. Depressive symptoms (measured using the seventeen-item Hamilton Rating Scale for Depression) and cognitive function (measured using the Montreal Cognitive Assessment) were assessed at baseline and the 12-month follow-up. Spearman's correlation was used to examine the correlation between cognitive function and depressive symptoms. Additionally, a cross-lagged panel analysis was employed to elucidate the causal relationship between these factors after adjusting for potential covariates.The results of a four-iteration cross-lagged panel analysis substantiated a bidirectional relationship between post-stroke depressive symptoms and cognitive function over time. Specifically, higher scores for early depressive symptoms were associated with lower scores for later cognitive function; additionally, higher baseline cognitive function scores were associated with lower depressive symptom scores at a later point.This study establishes a reciprocally causal long-term relationship between depressive symptoms and cognitive function after an ischemic stroke. Therefore, interventions aimed at improving cognitive function and ameliorating depressive symptoms may positively affect both cognition and mood.ChiCTR-ROC-17013993.Copyright © 2023 Elsevier Inc. All rights reserved.