Background: Methotrexate (MTX) is a chemotherapy drug associated with cognitive insufficiency in cancer patients treated with chemotherapy.Alpha lipoic acid (ALA) has been referred to as the "universal antioxidant" because of its unique antioxidant properties. Aim:to inspect the effect of MTX on the hippocampus and to correlate them with cognition impairment and to assess the neuroprotective role of ALA on hippocampus.. Materialsand methods:Thirty two male adult albino were classified into four groups: control group (physiologic saline), ALA group: ( 200 mg/kg orally for three weeks), MTX group:(250 mg/ kg)as a single dose of MTX intraperitoneally injected and MTX +ALA group: a single dose of intraperitoneal injection of MTX in the fourth day + ALA in a previous dose for three weeks starting from the first day. All rats were subjected to to Morris Water Maze testing to assess the hippocampus function. At the end of the experiment, all animals were anesthetized , cerebrum was removed to prepare the specimens for histological ,immunohistochemical and biochemical examination. Results:MTX caused impaired performance of Morris Water Maze of rats andbiochemical changes significant decrease intissueoxidative enzymes and increase in malondialdehyde (MDA) tissue levels. Moreover, MTXcaused histological changes in rat hippocampus in the form of degenerative and apoptotic neurons whichwas confirmed by immnnohistochemical staining of caspase -3 and GFAP staining and morphometrical analysis of pyramidal cell layer thickness and pyramidal cell count. Co-administration of ALAwith MTX significantly diminished the behavioural affection and biochemical changes and ameliorated the histological and immunohistochemicalchanges ofthe hippocampus. Conclusion:Our experimental results on albino rats proved the harmful effect of MTX on hippocampus tissue that explained the cognitive impairment associating MTX therapy and confirmedthe antioxidant and the antiapoptotic properties of ALA on hippocampustissue.This can be consideredclinically after suitable clinical evaluation