The current study examined whether the steroid hormone, 17β-estradiol (E2) can exert long-lasting beneficial effects upon axonal health, synaptic plasticity, dementia-related amyloid-beta (Aβ) protein expression, and hippocampal-dependent cognitive function in an animal model of chronic cerebral hypoperfusion and vascular dementia (VaD). Chronic cerebral hypoperfusion and VaD was induced by bilateral common carotid artery occlusion (BCCAO) in adult male Sprague Dawley rats. Low dose E2 administered for the first 3-months after BCCAO exerted long-lasting beneficial effects, including significant neuroprotection of hippocampal CA1 neurons and preservation of hippocampal-dependent cognitive function when examined at 6-months after BCCAO. E2 treatment also prevented BCCAO-induced damage to hippocampal myelin sheaths and oligodendrocytes, enhanced expression of the synaptic proteins synaptophysin and PSD95 in the hippocampus, and prevented BCCAO-induced loss of total and mushroom dendritic spines in the hippocampal CA1 region. Furthermore, E2-treatment also reduced BCCAO induction of dementia-related proteins expression such as p-tau (PHF1), total ubiquitin, and Aβ1-42, when examined at 6 m after BCCAO. Taken as a whole, the results suggest that low-dose E2 replacement might be a potentially promising therapeutic modality to attenuate or block negative neurological consequences of chronic cerebral hypoperfusion and VaD.