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Background/aim Alzheimer’s disease (AD) is a chronic neurodegenerative disease. The AD incidence is rising and is becoming a heavy economic burden on society and patients’ families. The present study was directed to investigate the protective and therapeutic effects of Hyphaene thebaica fruit extract (HTE) on AD in an animal model. Materials and methods A total of 90 adult albino male rats were involved in this study and were classified into six groups (15 each). Two negative control groups were used: one did not take any supplementation (G1) and a second negative control group in which normal rats were supplemented with HTE (G2). AD induction was performed by orally injecting the animals with 50 mg AlCl3/kg body weight for 6 weeks. Four groups took AlCl3. First group served as a positive control (G3). Two groups were used to investigate the effect of the orally injected HTE on AD rats either as a therapeutic (G4) or preventive (G5) agent. The last group was treated with the reference drug donepezil (G6). After treatment with HTE for 4 weeks, biochemical analyses of acetylcholinesterase activity, lipid peroxidation (malondialdehyde), and reduced glutathione were done in the brain tissue homogenate. Lipid profile was determined in sera. Expression level assessments of genes encoding microtubule-associated protein tau and amyloid precursor protein were carried out as well as DNA adducts were measured in brain tissues. Histopathological investigations of brain tissues were also performed. Results The results showed that brain samples of AD group exhibited significant changes in biochemical, molecular, and histopathological parameters. The samples of the groups treated with HTE showed improvements in the studied parameters. The treatment of induced AD group with HTE showed better results than supplementing the extract after occurrence of the signs of Alzheimer. Conclusion It was concluded that HTE acts as a promising candidate natural product to ameliorate and protect brain injury in AD-induced rats.