AbstractBackgroundSerpin is a superfamily of serine proteinase inhibitors. They have anticoagulative activities and immunoregulatory effects. The family has been widely studied in stroke patients and animal stroke models. However, results from clinical and preclinical studies are controversial. The systematic review and meta‐analysis aimed to determine whether serpin activities are affected by stroke and whether members of the serpin family could be used in stroke treatment.MethodsLiterature was systematically searched in six databases until September 5, 2022. In the included studies, 47 clinical studies (8276 subjects) reported concentrations of serpin proteins in stroke patients and healthy controls. In total, 41 preclinical studies (742 animals) reported neurological outcomes in animal models with serpin treatment and vehicle.ResultsMeta‐analysis of clinical studies showed that both ischemic (IS) and hemorrhagic stroke patients had higher thrombin‐antithrombin complex (TAT) levels and lower antithrombin (AT) levels which were persistent in the acute and subacute phase of IS. Meta‐analysis of preclinical studies reported the efficacy of serpins in treating stroke. C1‐INH and FUT175 reduced brain infarct size and improved sensorimotor and motor behavior in a dose‐ and time‐dependent manner in the MCAO models.ConclusionsOur study confirmed the important roles serpin family proteins played in the onset, progression, and treatment of stroke. Among serpins, AT and TAT may be used as blood biomarkers in the early diagnosis of stroke. C1‐INH and FUT175 could be potential medications for IS.