Stroke is a complex vascular and neurological syndrome that can lead to death and disability. The primary stroke injury is induced by the occlusion of directly supplied artery, and the secondary brain damage could be affected by the synaptic connections with the primary ischemic lesion. Tau protein is a microtubule associated cytoskeletal protein, expressed predominantly in neurons of the central nervous system. Tau protein plays a role in maintaining synaptic neuronal integrity and axonal transport, including promoting microtubule assembly and modulating stability of microtubules, which are regulated by tau phosphorylation state. Phosphorylated tau protein is induced by stroke. To investigate the role of human Tau protein in stroke, we employed female mice overexpressing normal human Tau (rTg(Tau)21221), female mice overexpressing P301L mutant human tau (rTg(TauP301L)4510, and age-matched female littermate wild type (WT) controls at 12 months old. Transient middle cerebral artery occlusion (tMCAO) was performed on diestrus as identified by virginal smears microscopically. Following a mild stroke injury of 30 min tMCAO, overexpression of normal human Tau significantly reduced infarction at 48 hours of reperfusion (P = 0.0157); following a moderate stroke injury of 60 min tMCAO, overexpression of normal human Tau also resulted in significantly reduced infarction compared to WT controls and mice expressing human tau with the P301L mutation (P = 0.0142). These novel data suggest that normal human Tau plays a protective role in acute stroke and support the view of targeting human tau as a new treatment for acute stroke.