INTRODUCTION: Post-stroke depression (PSD) is a severe complication of cerebrovascular stroke affecting about one-third of stroke survivors. Moreover, PSD is associated with functional recovery and quality of life (QOL) in stroke survivors. Screening for PSD is recommended. There are, however, differences in the literature on the impact of early screening on functional outcomes. In this systematic review, we synthesise the currently available literature regarding the associations between timing and setting of PSD screening and mortality, QOL and functional outcomes in stroke survivors. METHODS AND ANALYSIS: We will systematically search electronic databases including PubMed, Embase, APA PsycINFO, Web of Science, Scopus and CINAHL from inception to August 2021. Four reviewers will screen the title and abstract and full-text level records identified in the search in a blinded fashion to determine the study eligibility. Any selection disagreements between the reviewers will be resolved by the study investigator. Data extraction of eligible studies will be conducted by two reviewers using a predefined template. We will complete the quality assessment of included articles independently by two reviewers using the Newcastle Ottawa Scale. Eventual discrepancies will be resolved by the principal investigator. ETHICS AND DISSEMINATION: Due to the nature of the study design, ethical approval is not required. The systematic review and meta-analysis findings will be published and disseminated in a peer-reviewed journal. Our results will also be disseminated through posters and presentations at appropriate scientific conferences. PROSPERO REGISTRATION NUMBER: CRD42021235993.