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Cystatin C, a well‐established biomarker of renal function, has been associated with a protective effect against stroke. However, the potential neuroprotective mechanism of cystatin C in ischemic brain injury remains unclear. Our study hypothesized that cystatin C can ameliorate blood–brain barrier (BBB) disruption by up‐regulating caveolin‐1 expression, thereby improving neurological outcomes in cerebral ischemic injury. Western blotting, immunohistochemistry, immunofluorescence staining, and immunoprecipitation were performed to investigate target proteins. Evans Blue and gelatin zymography were used to examine the effect of cystatin C on BBB disruption. Plasmid and small interfering RNA transfection was used to observe alterations in caveolin‐1 and occludin expression induced by changes in cystatin C expression. Intriguingly, our study showed that the expression of both cystatin C and caveolin‐1 was increased in middle cerebral artery occlusion‐injured mice, and pretreatment with exogenous cystatin C significantly increased caveolin‐1 expression, reduced Evans Blue leakage in the injured brain region, and decreased the enzymatic activity of matrix metallopeptidase‐9. Meanwhile, our study also showed that the over‐expression of cystatin C greatly enhanced caveolin‐1 expression, which later increased occludin expression in oxygen‐glucose deprivation‐exposed brain microvascular endothelial cells. The knockdown of cystatin C induced the opposite outcomes. These experimental results indicate a positive role for cystatin C in the regulation of caveolin‐1 and occludin expression in cerebral ischemic injury. Taken together, these data unveil a new mechanism of the regulation of caveolin‐1 expression by cystatin C in the maintenance of BBB integrity after ischemic brain injury and provide new clues for the identification of potential therapeutic strategies for stroke. [ABSTRACT FROM AUTHOR]