Alzheimer's disease (AD) is a progressive and ultimately fatal neurodegenerative diseases. Aluminum, a neurotoxic metal, is considered as the pathological hallmark and contributing factor of AD. Hypericum perforatum extract (HPE) is a neuroprotective agent that can prevent neurodegenerative pathologies through antioxidants, anti-inflammatory and regulating neurotransmitter release in animal model of neuropathy. The present study aimed to identify the potential neuroprotective of HPE on AlCl₃-induced AD rats. Rats were treated with AlCl₃ for 90days to induce behavioral, biochemical, and neurochemical similar to AD. From 31thday, the rats were treated with HPE for 60days. Our results showed HPE improved cognitive function in AlCl₃-induced AD rats, and attenuated AlCl₃-induced increase in acetylcholinesterase activity and glutamic acid level as well as decreased in noradrenaline and dopamine level. In addition, HPE reversed AlCl₃-induced hippocampal pathology including amyloid-beta (Aβ) accumulation (elevated Aβ42 level and amyloid plaques), oxidative stress (increased reactive oxygen species level and thiobarbituric acid reactive substances level, decreased glutathione level and superoxide dismutase activity) and neuroinflammatory (increased mRNA expressions of Interleukin-1β, Interleukin-6, Tumor necrosis factor-α and major histocompatibility complex class II) in hippocampus of rats. Thus, HPE is conferred neuroprotection against AlCl₃-induced AD like pathology.