Alzheimer disease (AD) is a neurodegenerative disease which is characterized by the presence of extracellular senile plaques mainly composed of amyloid-β peptide (Aβ), intracellular neurofibrillary tangles, and selective synaptic and neuronal loss. AD brains revealed elevated levels of oxidative stress markers which have been implicated in Aβ-induced toxicity. Multiple components present in pomegranate and various pomegranate preparations are known to exert pleiotropic protective effects as demonstrated in various in vitro and in vivo model systems. The present study was designed to investigate the dietary supplementation of 4% pomegranate fruit grown in Oman on oxidative stress in the hippocampus, and hippocampal neuron injury in Tg2576 mice. The Tg 2576 mice were treated with 4% pomegranate by dietary supplementation for 15 months. After 15 months, the mice were sacrificed for measuring non-enzymatic [4-hydroxynonenal, TBARS, hydrogen peroxide, reduced glutathione (GSH), vitamin A, E, C and enzymatic antioxidants activity in the hippocampus, and expression of choline acetyltransferase (ChAT) positive neuron. The non-enzymatic and enzymatic antioxidants were significantly reduced along with elevated oxidative stress markers. Loss of ChAT positive neuron and severe damage to hippocampal neurons in Tg 2576 were also found. These abnormalities were significantly improved by 4% pomegranate treatment. In contrast, administration of 4% pomegranate diet to mice strongly suggested a putative delay in the formation of plaques, as indicated by a decreasing tendency of soluble and fibrillar Aβ levels in hippocampus which correlated with a decrease in Aβ (1-40, 1-42) plasma content. The study suggests that pomegranate could offer protection against neuronal injury and oxidative stress, and may be used as a potential agent in treatment of neurodegenerative diseases such as AD.